Copy Number Variations and Cognitive Phenotypes in Unselected Populations

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Supplementary Online Content

Katrin Männik K, Mägi R, Macé A et al. Copy Number Variations and Cognitive Phenotypes in Unselected Populations. JAMA. doi:

eMethods eTable 1. Phenotypes of EGCUT individuals with DECIPHER-listed recurrent rearrangements eTable 2. Prevalence and characteristic features of DECIPHER-listed genomic disorders eTable 3. Sample demographics and characteristics eTable 4. Summary scores of ALSPAC participants Standard Assessment Tests (SATs) eTable 5. Prevalence of NAHR-mediated recurrent CNVs in clinical and general population cohorts eTable 6. Follow-up phenotyping of 16p11.2 600kb BP4-BP5 deletions and duplications identified in the EGCUT cohort eTable 7. Individual CNVs in EGCUT discovery and replication cohorts eTable 8. Education attainment in EGCUT replication cohorts separately and combined with discovery cohort eTable 9. Mean Standard Assessment Tests (SATs) scores for English and Mathematics in ALSPAC CNV carriers eTable 10. Education attainment in Italian HYPERGENES cohort eTable 11. Education attainment in European American MCTFR cohort eTable 12. MetaCore Enrichment by GO Processes analysis report eFigure 1. Diagnoses reported in the EGCUT participants according to the WHO ICD-10 classification eFigure 2. Multidimensional scaling analysis of EGCUT population structure eFigure 3. Assessment of CNV deleteriousness

This supplementary material has been provided by the authors to give readers additional information about their work.

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eMethods

EGCUT The Estonian population was influenced by trends encountered by most of the European populations. Before the Second World War, Estonia had a relatively homogenous population (88% of ethnic Estonians in the 1934 population census) with strong cultural influence from previously ruling countries such as Germany, Sweden and Denmark. This make up was modified during the 1941 to 1991 Soviet Union occupation (i.e. mass deportations and executions of local people, flight of many Estonians, as well as of a majority of local German and Swedish minority members to Western Europe and Northern America in the 1940s, followed by implementation of a “russification” ideology). It resulted in the actual distribution of 69.7% Estonians, 25.2% Russians and 5.1% other minorities (2014 population census; Statistics Estonia, http://www.stat.ee/en). Religion plays a minor role in Estonia largely due to the Soviet occupation from 1941-1991 when “elimination of religion” was an ideological objective. As a result, Estonia is one of the least religious countries in the world – less than a third of the population defines itself as “believers”. The majority of these are Lutheran and Eastern Orthodox (Statistics Estonia, http://www.stat.ee/en). It is important to stress here that there is no restrictions to the accessibility of education in Estonia based on ethnicity or religious beliefs (see also below).

The Estonian Genome Centre of the University of Tartu (EGCUT) cohort is a longitudinal and prospective population biobank that contains close to 52,000 participants and represents 5% of the Estonian adult population. The long-term recruitment via general practitioners and a widespread network of special recruitment offices (rather than self-initiated and/or web-based) has granted that the samples have been collected throughout the country and diverse social groups. The resulting representation of a wide range of phenotypes (eFigure 1), age and educational groups makes the cohort ideally suited to population-based studies. The distribution of participants’ geographical origin, age, sex and achieved education level closely reflects those of the Estonian population in general. At baseline, the general practitioners (GPs) performed a standardized objective examination of the participants, who also donated blood samples for DNA, white blood cells and plasma tests and filled out a 16-module questionnaire that encompass more than 1000 health- and lifestyle-related questions, as well as uniformed report of clinical diagnoses according to the World Health Organization international classification of diseases (WHO ICD-10, http://www.who.int/classifications/icd). The data are continuously updated through follow-up interviews, as well as national electronic health databases and citizen registries (see1 and www.biobank.ee for details). Analyses of participants’ age, gender, diseases and educational level show that this cohort is representative of the country’s population. EGCUT is conducted according to Estonian Human Genes Research Act and managed in conformity with the standard ISO 9001:2008. The Ethics Review Committee on Human Research of the University of Tartu approved the project. Written informed consent was obtained from all voluntary participants for the baseline and follow-up investigations.

All population carriers of 16p11.2 600kb BP4-BP5 (breakpoint) recurrent copy number variants (CNVs) were invited back for follow-up investigations using the clinical and neuropsychological protocol previously used to study 16p11.2 syndrome patients ascertained through clinical cohorts2,3.

The EGCUT cohort (and Estonian population in general) is an outbred population with no substantial regional differences. Single-nucleotide polymorphism (SNP) allele frequencies and linkage disequilibrium patterns are similar to the one found in populations with European ancestry4. We do not find small series of non-recurrent CNVs and/or inflation of recurrent rearrangements typical of founder effects5,6 (see also CNV calling section below). Accordingly, its samples have been successfully used to discover or replicate hundreds of SNP associations, which are vulnerable to population frequencies and stratification differences (e.g. genome wide association studies on education attainment, adult height and age of menarche7-9. Of note all quality control (QC) procedures suggested in 10 were applied to results submitted by the EGCUT cohort in these meta-analyses and no problems were uncovered.

The identity-by-descent of EGCUT participants was estimated using SNP genotypes and PLINK software. 14.6% and 5.9% of discovery and replication cohort individuals show cryptic relatedness (pi_hat >0.15) on par with enrolling 5% of the population. To exclude the possibility that the EGCUT cohort could be affected by hidden population stratification, multidimensional scaling (MDS) analysis was performed using PLINK1.07 (http://pngu.mgh.harvard.edu/~purcell/plink/strat.shtml). SNPs that passed quality control from a full set of genotyped EGCUT samples were pruned so that all SNPs

Downloaded From: https://jamanetwork.com/ on 09/26/2021 within a given window size of 50 had pairwise r2 < 0.5. Pairwise IBS (identical by state) distance was calculated using all autosomal SNPs that remained after pruning. MDS dimensions were extracted using the "MDS-plot" option. R 3.0.2 was used for plotting and visualization of the results. This analysis demonstrated that genetic stratification could not lead to the observed associations (eFigure 2). No differences were observed upon exclusion of pairs with high relatedness (>0.1).

CNV calling The genomic DNA of 8110 subjects (7020 for the discovery and 1090 for the replication cohort) was randomly selected among the 52,000 EGCUT participants. A third cohort of 1066 individuals (“high- functioning replication cohort”) was used to further assess the significance of the signal obtained regarding education attainment.

The three cohorts were selected and SNP genotyped at three different time-points over a period of four years using Illumina HumanOmniExpress (discovery cohort) and Illumina Human CNV370 BeadChips (both replication cohorts) (Illumina Inc., San Diego, CA; USA). The HumanOmniExpress BeadChip covers the entire human genome with median spacing of 2.1 kb and the HumanCNV370 BeadChip has a genome-wide median spacing of 5 kb. All samples were processed and the assay performed according to a routine protocol provided by the manufacturer. Genotypes were called by GenomeStudio software GT module v3.1 (Illumina Inc). Log R ratio (LRR) and B Allele Frequency (BAF) values produced by the GenomeStudio software were formatted for further CNV calling with Hidden Markov Model-based software PennCNV (ver. June 2011)11 using the parameters suggested by the software authors together with “GC model adjustments” and “Merging adjacent CNV calls” function. The 6819 discovery, 1058 replication and 993 “high-functioning” replication samples with a call rate greater than 98% and less than 50 CNV calls that passed the quality control parameters were retained. To minimize the number of false positive findings, CNVs ≥250kb in size were filtered for the PennCNV confidence score ≥30 (HumanOmniExpress) or ≥40 (HumanCNV370) and visual confirmation in GenomeStudio GenomeViewer. As >1Mb rearrangements have a high likelihood of having pathogenic effect, we used an initial size threshold of 1Mb for both types of CNVs and subsequent series of thresholds half this size (500kb, 250 kb and 125kb) until loss of the association. The genotype of 23 carriers of DECIPHER-listed CNVs was assessed by quantitative PCR and resulted in no false positive findings. The EGCUT genotyping facility is licensed to use the same procedure to provide SNP-array genotyping for diagnostic purpose to the Medical Genetics Center of Tartu University Hospital. This method identified CNVs in 298 individuals in a cohort of 1191 patients referred to clinical geneticists, all of which were subsequently validated by quantitative PCR12. All QC filtered CNVs were used in CNV frequency calculation within the human genome. All CNVs were mapped chromosome-wise into matrices, where each CNV start and end marker was used as a row and each sample as a column. Within these matrices, all partial CNV overlaps between samples were recorded and their frequency was measured as the proportion of samples having CNV in this region out of all samples (including samples without any CNVs) using a custom Perl script.

Individuals carrying more than one large rare CNV were manually reviewed and classified according to the largest imbalance. CNV calls of individuals who carried both a deletion and a duplication (n=14) were carefully annotated and grouped according to the most likely pathogenic CNV. The individual who carried a pathogenic 1.9Mb duplication along with a 250 kb deletion encompassing no genes was included in the ≥1Mb duplications group, while the remaining 13 individuals carried pairs of rare CNVs with no evidence of potential pathogenicity. Due to the generally more deleterious nature of deletions the latter were included in the group of deletion carriers. As they all had completed at least secondary education and lacked noteworthy diagnoses, they had no positive influence on the signal in the deletion group. Ten other individuals carried more than one rare deletion. Seven of these were older than 50 years and two had diagnosis of a neoplasm. Presence of an additional rare genomic alteration had no impact on their cognitive function (mean education level (MEA) = 4.4; less than secondary education = 20%). All these individuals were classified according to the largest deletion. All individual primary and additional CNVs identified in discovery and replication cohorts are listed in eTable 5.

To evaluate if the EGCUT deletions were specific to the Estonian population we compared them with the tier 1 heterozygous deletions identified in the comprehensive clinical cohort of 21,470 individuals of the Baylor College of Medicine13. Despite different filtration approaches, e.g. Boone et al. “filtered for only CNVs that affect at least one recessive Mendelian disease genes and not any genes associated with dominant disorders or complex inheritance patterns”, while our filtration was based on CNV size and population frequency, we found that 23.4% or 67 out of 286 individual rare deletions (size range

Downloaded From: https://jamanetwork.com/ on 09/26/2021 250 kb - 2.67 Mb, median size 429 kb; 39 different loci 4 of which are DECIPHER-listed) in our Estonian population cohort have a complete overlap with unique recessive deletions in the Baylor dataset (combining CNVs with identical breakpoints and Baylor CNV completely encompassed in EGCUT CNV). This confirms that the EGCUT variants are widespread rather than population specific. It further suggests that the signals we observe are not merely established by enrollment or phenotyping biases.

Genotype-phenotype correlations The age, gender and education distributions of both the EGCUT discovery and replication cohorts correspond to those of the Estonian general population. Although the age range of the 56 DECIPHER- listed rearrangement carriers spanned from 19 to 83 years, their mean age was 8 years below that of the EGCUT cohort (41.9 versus 49.1 years). Such a difference was absent if we considered all the rare CNV carriers.

As the prevalence of ICD-10 disease category “infectious and parasitic diseases” (A00-90 in the WHO ICD-10) is large enough for statistical analysis (eFigure 1) and expected to be independent of CNV carrier status, we used this value as an additional internal control to assess random phenotype fluctuations in all our analyses. As anticipated, the prevalence of infectious diseases, which was 22.9% in the EGCUT cohort, showed only minor changes in all CNV-stratified sample sets. To estimate the inclusion of somatic variants in our data set, we used the prevalence of malignant neoplasms (C00-C97 in the WHO ICD-10) as a proxy. When compared with EGCUT (6.4%), the prevalence of neoplasms stayed unchanged amongst carriers of DECIPHER-listed CNVs (6.9%), ≥250 kb deletion (6.5%) and duplication (5.5%) carriers. It is, however, higher in groups of ≥500 kb CNVs until 13.9% (OR=2.4, P=0.08) ≥1Mb deletion carriers. Since the somatic nature of these CNVs remained hypothetical, these carriers were not excluded from our analyses. As they did not show cognitive or developmental problems they had no false positive impact on the results.

Intellectual disability is defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM- IV) as a deficit in overall cognitive functioning along with limitations in adaptive behavior. It was diagnosed as described in F70-79 of the WHO ICD-10 and recorded in participants’ medical history before enrollment to the biobank. It is reported to the EGCUT questionnaire by the recruiting GPs. Its prevalence is estimated at 1-3% in developed countries14, which is consistent with the prevalence found in EGCUT discovery cohort (1.7%).

Education levels were coded according to the Estonian education curriculum: 1 - less than primary; 2 - primary (currently 3 years); 3 – basic (currently 9 years, includes basic education for children with special needs); 4 – secondary (currently 12 years, includes vocational secondary); 5 – professional higher/college; 6 – university/academic degree; 7 – scientific degree (MSc and PhD). As several education reforms in Estonia’s recent history have changed the duration of all basic, secondary and tertiary levels, “the highest completed education level” instead of “years of schooling” was used as a measure for each individual. In both the discovery and random replication cohorts the mean education attainment (MEA) corresponded to the secondary education (MEA = 4.09 and 4.0, respectively) in agreement with the country’s MEA. Due to the recruitment criteria that required participants to provide sufficient and consistent information in an advanced sleeping pattern-related questionnaire and a regular work schedule over a survey period of six months, the “high-functioning replication cohort” was biased towards higher than average socio-cognitive functioning (MEA=4.77, lower than secondary education 9.4%). Correspondingly, this group was depleted of DECIPHER-listed CNV carriers (7 expected/2 observed; one of these individuals is a carrier of the 17p12 duplication causative for Charcot-Marie-Tooth syndrome Type 1A (Online Mendelian Inheritance in Man database (OMIM) #118220) known not to affect cognitive functioning). Due to this recruitment bias these DECIPHER carriers were not included in our study of the recurrent syndromic CNVs in the general population. For the same reasons the results of the high-functioning replication cohort were only used in downstream replication analysis (see Results section).

The Estonian population is highly literate. Briefly, by the end of the 19th century between 70 and 80% of the population was able to read and write. This fraction grew steadily and encompasses now 99.8% of the population (2011 census of population age 15 and over) placing the Baltic nation among the most literate population in Europe and the world. This strong emphasis on “education for all” is centrally managed by the Ministry of Education and Research (https://www.hm.ee/en). Primary and lower secondary education is organized as a single structure system. It starts at 7 years of age and

Downloaded From: https://jamanetwork.com/ on 09/26/2021 consists of nine years of mandatory schooling. While upper secondary education is not compulsory, the vast majority of the population participates (in 2013, approximately 70% of the graduates of basic school continued with upper secondary education). Adult upper secondary school provides all adults who did not complete their studies an opportunity to acquire secondary education (The European Encyclopedia of National Education Systems: https://webgate.ec.europa.eu/fpfis/mwikis/ eurydice/index.php/Estonia; The educational statistics database of Estonia: http://www.haridussilm.ee; The Ministry of Education and Research of Estonia: https://www.hm.ee).

According to the “Basic Schools and Upper Secondary Schools Act”, all schooling costs are covered by the school manager, which means that schools are public and without tuition fee. While homeschooling is allowed at the basic school level it is uncommon. The number of private schools remains extremely modest with 2% of the total number of schools and contrary to the situation in the U.S.A and the U.K. these do not present more elitarian schooling similar to what is found in other continental European countries. Similarly, the majority of the universities and professional higher education institutions run under public law. They provide for qualified education without tuition fee. Students can apply for monthly allowances and special study loans at all academic levels (The Ministry of Education and Research of Estonia: https://www.hm.ee).

Although several reforms have been introduced to the Estonian education system during the 20th century, a well-functioning and up-to-date national system of general education was already established in the Estonian Republic before the Second World War. Although it was re-organized to make it compatible with the Soviet centralized ideological principles of education, the system maintained its structure and easy accessibility throughout the Soviet era. During the Soviet occupation and in relation to a massive immigration, the Russian language was imposed in parallel to (and often instead of) Estonian in official use. Accordingly education was based on both Russian and Estonian curricula. Since the fall of the Soviet Union and the regained independence in 1991, the schooling in Russian with Estonian as the second language is still provided for native Russian speakers according to the Estonian government policy at integrating children, adolescents and adults whose mother tongue is other than Estonian into the Estonian society15.

The OECD (Organisation for Economic Co-operation and Development) Program for International Student Assessment (PISA; http://www.oecd.org/pisa) survey assesses the learning competences of 15- year-olds in 510,000 randomly selected students from 65 countries, representing about 28 million students globally. According to the PISA 2012 survey the Estonian education is among the best in the world. Based on average results on global scale, Estonian students are in 6th place in science and 11th place in math and reading. In all three tested subjects the average results of Estonian students are significantly above the average of the OECD member countries (i.e. the group of most developed countries in the world) and among the absolute top of Europe (1st place in science, 3rd in math and reading). Further confirming that differences in education possibilities due to religion or ethnicity could not be at the base of the observed association between CNVs and attained education, the PISA comparisons of performance levels (i.e. equality between students) showed that Estonia is: i) the number one country in the world in equal results in science (i.e. with the smallest fraction of poorly performing students in the world); and ii) the number one country in Europe in equal results in math and reading (i.e. with the smallest number of students who have not acquired at least baseline level of the subject). For more details on this subject see for example the discussion on education performance, equity and efficiency at http://www.ncee.org/2015/01/statistic-of-the-month-education-performance- equity-and-efficiency/). The OECD Program for the International Assessment of Adult Competencies (PIAAC; http://www.oecd.org/site/piaac/surveyofadultskills.htm) performed analogous surveys in adults. It assesses 16 to 65-years-old people for key cognitive and workplace skills typically required in the 33 OECD members’ economies. According to the PIAAC 2013 report the literacy and numeracy of Estonian adults is above the average of the OECD member countries. In comparison with the other OECD countries, gender and other differences in literacy and numeracy are small in the Estonian population.

Information about the prevalence of recurrent genomic syndrome regions, was obtained from the DECIPHER (http://decipher.sanger.ac.uk), Orphanet (http://www.orpha.net/consor/cgi-bin/index.php), OMIM (http://www.omim.org), the NCBI collection of disorder reviews GeneReviewsTM (http://www.ncbi.nlm.nih.gov/books/NBK1116) databases, the Unique – Understanding Chromosome Disorders disorder guides (http://www.rarechromo.org/html/DisorderGuides.asp) and peer-reviewed literature. The prevalence of the 57 autosomal syndromes listed in DECIPHER was calculated

Downloaded From: https://jamanetwork.com/ on 09/26/2021 assuming that one individual has only one disease. The resulting expected prevalence of autosomal DECIPHER syndromes amounted to 85 individuals in 10,000 for all genomic disorders, 21 in 10,000 for highly pathological anomalies (grade 1 and 2) and 64 in 10,000 for variable syndromes and susceptibility loci (grade 3 and ungraded; eTable 2). Of note, 5 out of 6 diagnosed grade 1 DECIPHER-listed syndromes in our cohort are peripheral neuropathies – Charcot-Marie-Tooth syndrome Type 1A (OMIM #118220) and hereditary neuropathy with liability to pressure palsies (OMIM #162500) with no impact on cognition.

We analyzed the difference of studied phenotypes between CNV carriers and population. Fisher’s two- sided exact tests and Welch two sample t-test were used for statistical analysis in The R Project for Statistical Computing environment (http://www.r-project.org; R version 3.0.2). Odds ratios, 95% confidence intervals and P-values were calculated; a threshold of 5% was set to indicate statistical significance.

Assessment of CNV deleteriousness and function Each CNV was annotated using the ENSEMBL Genebank Annotation file with Human genome release Homo sapiens GRC h37.74. For this purpose the CNV genomic coordinates were lifted from build 36 to build 37 using the Batch Coordinate Conversion (LiftOver) tool from the UCSC website (http://genome.ucsc.edu/cgi-bin/hgLiftOver). The Neurodevelopmental Gene list (ND-genes) was described in 16,17. To establish their list of 1560 ND-genes they grouped i) genes associated with the terms “mental retardation” “intellectual disabilities”, “autism”, “schizophrenia”, “psychosis”, and “epilepsy” in OMIM database, ii) SFARI autism candidate genes with association scores ranging from 1 to 4 (https://sfari.org/) and iii) all candidate genes mapping in known genomic disorders intervals 18. The haploinsufficiency scores (HiS), i.e. the probability that a given gene maintains its normal function only with two functional copies, were obtained from 19. Using their values, we calculated two measures for each CNV: i) the sum of the HiS of all the embedded imbalanced genes and ii) the largest HiS of the encompassed genes. Ohnologs are paralogous genes resulting from ancestral whole-genome duplication events. They comprise about 30% of protein-coding genes in the human genome and have recently been shown to be dosage balanced, associated with diseases 20 and overrepresented in pathogenic CNVs 21. The list of ohnologs used in this study was obtained from 20. Regulatory elements were retrieved from 22 and grouped in different chromatin states data from lymphoblastoid cell line GM12878, i.e. promoter-, enhancer-, insulator- and transcriptional element classes. We computed the number of chromatin states embedded into each CNV using the bedops software 23 and calculated the Spearman correlation between education level and these counts for each chromatin states using the R function cor.test(). We also assessed the correlation between the total number of elements of the four different states and the education level to get a global correlation p-value.

For enrichment analyses, listing of all protein-coding genes encompassed by deletions (≥250 kb, carrier frequency ≤0.05%) resulted in 642 genes. To assess the function of imbalanced genes we used Thomson Reuters MetaCore™ (version 6.18), an integrated software suite for data-mining and pathway analysis based on a manually-curated biological knowledge database. It uses the submitted dataset of gene IDs for creating a list of network objects (n=690 in the current set) and mapping these on functional ontologies represented by pathway maps and networks to find significant enrichments. We used for these analyses only the discovery cohort as it provides better breakpoint resolution due to the higher-density genotyping platform.

ALSPAC cohort The Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort based in Bristol, UK 24. 14,541 pregnant women with expected delivery dates between 1st April 1991 and 31st December 1992 were initially enrolled. 13,988 children who were alive at 1 year of age, and additional families were enrolled in later phases. Detailed phenotypic information on the children and their parents were collected during clinic visits and by completion of questionnaires, as well as from linkage with external data sources. The ALSPAC study website contains details of all the data available through a fully searchable data dictionary at: http://www.bris.ac.uk/alspac/researchers/data-access/data- dictionary/. Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.

A total of 9912 subjects were genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform by 23andMe subcontracting the Wellcome Trust Sanger Institute, Cambridge, UK and the Laboratory Corporation of America, Burlington, NC, USA (http://www.bristol.ac.uk/media-

Downloaded From: https://jamanetwork.com/ on 09/26/2021 library/sites/alspac/migrated/documents/gwas-data-generation.pdf). Individuals were excluded from further analysis on the basis of having incorrect gender assignments; minimal or excessive heterozygosity (0.345 for the Sanger data and 0.330 for the LabCorp data); disproportionate levels of missingness per individual, i.e. the number of SNP markers with missing genotype per individual (>3%); evidence of cryptic relatedness (>10% IBD) and being of non-European ancestry (as detected by a multidimensional scaling analysis seeded with HapMap 2 individuals, EIGENSTRAT analysis revealed no additional obvious population stratification and genome-wide analyses with other phenotypes indicate a low genomic inflation factor λ). The 5218 genotyped unrelated samples with education information (of which 5160 had Mathematics and 5022 had English standard assessment tests (SATs) scores) who passed quality control and who gave consent were retained for analysis (Table 1). The middle tertile was not analyzed for the logistic regression analysis. Numbers in tertiles are shown in eTable 4.

Generation of Log R Ratio (LRR) and B Allele Frequency (BAF) metrics in ALSPAC were described previously 25. Briefly, Intensity Data files and computed LRR and BAF were not available for ALSPAC. Normalized probe intensities were used to estimate LRR and BAF using the approach described in 26. Reference genotype clusters were derived from the whole cohort (a representative population sample). LRR was computed as the ratio of normalized intensity of a sample to expected intensity (based on linear interpolation of reference genotype cluster intensities for that allelic ratio). BAF was computed as relative position of sample allelic ratio between homozygote (allele dose 0.0/1.0) and heterozygote (allele dose 0.5) reference clusters. PennCNV was used to call CNVs using the default parameters. CNV quality control was based on a quality score combining several PennCNV outputs (confidence score, number of probes, CNV length, number of CNV per sample, LRR standard deviation, BAF drift, BAF standard deviation, BAF mean, Waviness factor) optimizing the filtering of the true CNVs. Individuals with more than 200 CNVs were discarded.

HYPERGENES cohort The HYPERGENES cohort encompasses 451 individuals for which education levels information are available. These individuals were initially ascertained as normotensive 27. Years of schooling are defined in accordance with the International Standard Classification of Education (ISCED; http://www.uis.unesco.org/Education/Pages/international-standard-classification-of-education.aspx) 1997 classification, leading to seven categories of education attainment internationally comparable: 0 – Pre-primary education; 1 – Primary education or first stage of basic education; 2 – Lower secondary or second stage of basic education; 3 – (Upper) secondary education; 4 – Post-secondary education; 5 – First stage of tertiary education (not leading directly to an advanced research qualification); 6 – Second stage of tertiary education (leading to an advanced research qualification, e.g. a PhD)

Genotyping was performed on Illumina 1M-Duo BeadChips capturing 1,199,187 SNPs. Log R ratio (LRR) and B Allele Frequency (BAF) values produced by the GenomeStudio software were formatted for further CNV calling with Hidden Markov Model-based software PennCNV (ver. June 2011)11. CNV quality control and filtration was performed as described above. Differences in means of educational attainment were compared using Wilcoxon rank-sum test and Welch two samples t-test were used for statistical analysis in “The R Project for Statistical Computing environment” (http://www.r-project.org; R version 3.0.2). Both methods returned comparable P-values.

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 1. Phenotypes of EGCUT individuals with DECIPHER-listed recurrent rearrangements

Case SNP array result Length Genes Syndrome Gender, Education BMI Reported neuropsychiatric, congenital Formatted Table (Mb) Age anomalies and features characteristic to the syndrome (if known) Genomic disorders with DECIPHER grade 1 and 2

1 arr 7q11.23(72,360,917- 1.4 24 Williams-Beuren M, 37y 2 25.0 I10 (essential hypertension); short stature (165 73,739,845)x1 syndrome (elementary) cm, -2.68 SD); currently disability pesnioneer 2 arr 17p12(14,041,753- 1.4 8 Hereditary Liability F, 47y 3 (basic) 19.2 G54 (nerve root and plexus disorders), self-report 15,411,904)x1 to Pressure Palsies of moderate anxiety/depression 3 arr 17p12(14,041,753- 1.4 8 Hereditary Liability F, 40y 5 25.3 Not reported 15,411,904)x1 to Pressure Palsies (professional college) 4* arr 17p12(14,041,963– 1.4 7 Charcot-Marie-Tooth M, 33y 4 23.9 G60.0 (hereditary motor and sensory neuropathy); 15,390,352)x3 syndrome Type 1A (secondary) self-report of severe pain/discomfort and problems with daily duties 5 arr 17p12(14,041,753– 1.4 8 Charcot-Marie-Tooth M, 62y 3 (basic) 29.5 Not reported 15,411,904)x3 syndrome Type 1A 6 arr 17p12(14,057,122– 1.4 7 Charcot-Marie-Tooth M, 55y 3 (basic) 29.1 M75 (other soft tissue disorders, shoulder lesions); 15,411,904)x3 syndrome Type 1A M15 (polyarthrosis); self-report of moderate pain/discomfort Genomic disorders with DECIPHER grade 3 and ungraded

7* arr 1q21.1(144,109,304– 0.3 15 1q21.1 TAR M, 21y 4 19.9 Not reported 144,458,820)x1 susceptibility locus (secondary) 8 arr 1q21.1(144,106,312- 0.4 15 1q21.1 TAR F, 41y 4 33.7 F41.1 (generalized anxiety disorder); M42 (spinal 144,474,316)x1 susceptibility locus (secondary) (Obese class I) osteochondrosis) 9 arr 1q21.1(144,337,336- 0.2 4 1q21.1 TAR F,57y 6 (university 38.3 E66.9 (adiposity); F41.0 (panic disorder); F48.8 144,519,174)x1 susceptibility locus degree) (Obese class (neurotic disorder); Self-assessment of severe II) anxiety/depression 10 arr 1q21.1(144,337,336- 0.2 4 1q21.1 TAR M, 21y 5 27.2 Self-assessment of moderate anxiety/depression 144,519,174)x1 susceptibility locus (professional college) 11 arr 1q21.1(144,800,611- 1.5 13 1q21.1 deletion M, 59y 3 (basic) 24.8 Self-assessment of moderate anxiety/depression 146,325,568)x1 syndrome and problems with daily duties 12 arr 1q21.1(144,800,611- 1.5 13 1q21.1 deletion M, 77y 5 27.8 Self-assessment of moderate anxiety/depression 146,325,568)x1 syndrome (professional and problems with daily duties college) 13 arr 1q21.1(144,967,972- 1.4 12 1q21.1 deletion M, 52y 4 30.0 Not reported 146,325,568)x1 syndrome (secondary) (Obese class I)

Downloaded From: https://jamanetwork.com/ on 09/26/2021 14 arr 1q21.1(144,800,611- 1.5 13 1q21.1 duplication F, 28y 4 18.0 M08 (juvenile arthritis) 146,262,563)x3 syndrome (secondary) (Mild thinness) 15 arr 1q21.1(144,967,972- 1.3 12 1q21.1 duplication M, 34y 4 23.0 F45.3 (somatoform autonomic dysfunction) 146,262,563)x3 syndrome (secondary) 16* arr 1q21.1(144,970,329– 1.3 12 1q21.1 duplication M, 56y 3 (basic) 30.1 Not reported 146,293,282)x3 syndrome (Obese class I) 17 arr 1q21.1(145,020,771- 1.4 12 1q21.1 duplication F, 63y 3 (basic) 31.2 Early menopause (age 38y) 146,377,870)x3 syndrome (Obese class I) 18 arr 1q21.1(145,022,717- 1.3 12 1q21.1 duplication F, 32y 4 21.9 Not reported 146,286,966)x3 syndrome (secondary) 19 arr 1q21.1(145,114,847- 1.2 11 1q21.1 duplication M, 71y 3 (basic) 29.7 Self-assessment of moderate anxiety/depression 146,325,568)x3 syndrome 20* arr 3q29(197,219,312– 1.6 21 3q29 duplication M, 29y 2 24.2 Self-assessment of moderate anxiety/depression 198,830,963)x3 syndrome (elementary) 21 arr 7q11.23(72,360,917- 1.4 24 7q11.23 duplication F, 32y 3 (basic) 23.8 F20 (schizophrenia); F70.1 (mild mental 73,776,539)x3 syndrome retardation with significant impairment of behaviour); M41 (infantile idiopathic scoliosis); Self-assessment of inability to manage daily duties; currently disability pesnioneer 22 arr 8p23.1(8,131,816- 4.1 27 8p23.1 deletion F, 37y 3 (basic) 29.7 F32 (depressive episode); F45.0 (somatization 12,249,050)x1 syndrome disorder); F70.1 (mild mental retardation with significant impairment of behaviour); G40 (epilepsy); I49 (cardiac arrhythmia); Q21.3 (Tetralogy of Fallot); early menopause (age 35y); Self-assessment of problems with daily duties; currently disability pesnioneer 23 arr 15q13.2q13.3(28,686,425- 1.6 7 15q13.3 deletion F, 29y 3 (basic) 25.0 N97 (female infertility) 30,301,633)x1 syndrome 24 arr 15q13.2q13.3(28,750,112- 1.6 7 15q13.3 deletion F, 19y 3 (basic) 29.6 C69.2 (malignant neoplasm of retina) 30,301,633)x1 syndrome 25 arr 16p13.11(14,876,360– 1.3 13 16p13.11 recurrent M, 83y 3 (basic) 23.2 Self-assessment of moderate anxiety/depression 16,199,483)x1 deletion 26 arr 16p13.11(15,400,547– 2.7 12 16p13.11 recurrent M, 51y 3 (basic) 25.1 Self-assessment of inability to manage daily duties 18,072,199)x1 deletion and moderate anxiety/depression; currently disability pesnioneer 27 arr 16p13.11(15,000,279– 1.2 11 16p13.11 recurrent M, 60y 5 28.0 Q63.1 (lobulated, fused or horseshoe kidney); self- 16,210,889)x3 duplication (professional assessment of moderate anxiety/depression college) 28 arr 16p13.11(15,000,279– 1.2 11 16p13.11 recurrent F, 29y 6 (university 25.2 G24 (dystonia) 16,210,889)x3 duplication degree) 29 arr 16p13.11(15,000,279– 1.2 11 16p13.11 recurrent M, 31y 2 23.7 F71.1 (moderate mental retardation with significant 16,210,889)x3 duplication (elemetary) impairment of behaviour); currently disability pesnioneer

Downloaded From: https://jamanetwork.com/ on 09/26/2021 30 arr 16p13.11(15,034,391– 1.2 11 16p13.11 recurrent F, 21y 4 20.1 F50.9 (unspecified eating disorder); Q24.8 (other 16,210,889)x3 duplication (secondary) specified congenital malformation of heart) 31 arr 16p13.11(15,034,391– 1.2 11 16p13.11 recurrent F, 42y 4 39.1 F41.0 (panic disorder) 16,210,889)x3 duplication (secondary) (Obese class II) 32 arr 16p13.11(15,034,391– 1.2 11 16p13.11 recurrent M, 49y 7 (scientific 23.8 Not reported 16,210,889)x3 duplication degree) 33 arr 16p13.11(15,793,744– 2.3 8 16p13.11 recurrent F, 72y 3 (basic) 22.4 F33.1 (recurrent depressive disorder); F51 18,072,199)x3 duplication (nonorganic sleep disorder) 34 arr 16p13.11(15,793,744– 2.3 8 16p13.11 recurrent M, 37y 3 (basic) 31.7 Not reported 18,072,199)x3 duplication (Obese class I) 35 arr 16p13.11(15,400,547– 2.8 12 16p13.11 recurrent M, 61y 3 (basic) 37.7 Self-assessment of moderate anxiety/depression; 18,173,848)x3 duplication (Obese class currently disability pesnioneer II) 36 arr 16p13.11(15,400,547– 3.1 15 16p13.11 recurrent F, 32y 4 36.6 Not reported 18,513,898)x3 duplication (secondary) (Obese class II) 37 arr 16p13.11(15,000,279– 1.1 10 16p13.11 recurrent M, 39y 4 38.2 Not reported 16,060,440)x3 duplication (secondary) (Obese class II) 38* arr 16p13.11(15,032,942– 1.2 11 16p13.11 recurrent M, 28y 4 26.8 Not reported 16,198,600)x3 duplication (secondary) 39* arr 16p13.11(15,032,942– 1.2 11 16p13.11 recurrent M, 35y 4 31.0 Q85 (phakomatosis) 16,198,600)x3 duplication (secondary) (Obese class I) 40* arr 16p13.11(15,032,942– 1.2 11 16p13.11 recurrent F, 32y 4 31.2 F32 (depressive episode) 16,198,600)x3 duplication (secondary) (Obese class I) 41* arr 16p11.2(29,502,984– 0.6 27 16p11.2 deletion M, 22y 3 (basic) 35.9 F32 (depressive episode); G25.2 (specified forms 30,085,308)x1 syndrome (Obese class of tremor); G40.9 (unspecified epilepsy); self- II) assessment of moderate anxiety/depression 42 arr 16p11.2(29,320,004– 0.8 31 16p11.2 deletion F, 40y 4 37.2 Self-assessment of moderate anxiety/depression 30,105,652)x1 syndrome (secondary) (Obese class and problems with daily duties II) 43 arr 16p11.2(29,502,984– 0.5 27 16p11.2 deletion M, 32y 3 (basic) 30.1 F48 (neurotic disorder); F71 (moderate mental 30,033,300)x1 syndrome (Obese class I) retardation); F98.0 (nonorganic enuresis); M08 (juvenile arthritis) 44 arr 16p11.2(29,502,984– 0.6 31 16p11.2 deletion F, 35y 3 (basic) 34.9 E28 (ovarian dysfunction); E66 (obesity); I10 30,123,121)x1 syndrome (Obese class I) (essential hypertension); I42 (cardiomyopathy) 45* arr 16p11.2(29,502,984– 0.6 27 16p11.2 duplication F, 24y 3 (basic) 19.1 Self-assessment of severe anxiety/depression and 30,085,308)x3 syndrome problems with daily duties 46* arr 16p11.2(29,502,984– 0.7 31 16p11.2 duplication F, 20y 3 (basic) 17.6 G40 (epilepsy); Q21 (congenital malformations of 30,195,224)x3 syndrome (Mild thinness) cardiac septa); self-assessment of problems with daily duties 47 arr 16p11.2(29,568,718– 0.5 27 16p11.2 duplication M, 59y 4 25.8 Not reported

Downloaded From: https://jamanetwork.com/ on 09/26/2021 30,054,765)x3 syndrome (secondary) 48 arr 16p11.2(29,779,861– 0.3 18 16p11.2 duplication F, 70y 2 22.7 Not reported 30,095,177)x3 syndrome (elementary) 49 arr 16p11.2(29,779,861– 0.3 18 16p11.2 duplication M, 37y 4 24.2 Not reported 30,095,177)x3 syndrome (secondary) 50 arr 16p11.2(29,835,203– 0.2 15 16p11.2 duplication F, 37y 4 18.8 Not reported 30,054,765)x3 syndrome (secondary) 51 arr 16p11.2(29,869,853– 0.3 18 16p11.2 duplication M, 67y 6 (university 26.0 Not reported 30,123,121)x3 syndrome degree) 52* arr 22q11(17,118,296– 2.7 51 22q11 duplication M, 45y 3 (basic) 22.4 N62 (gynecomastia); self-assessment of moderate 19,792,353)x3 syndrome pain/discomfort and problems with daily duties 53 arr 22q11(17,266,915– 2.5 51 22q11 duplication M, 44y 4 31.2 F06.7 (mild cognitive disorder); H81 (disorders of 19,793,730)x3 syndrome (secondary) (Obese class vestibular function); self-assessment of moderate II) pain/discomfort and problems with daily duties 54 arr 22q11(17,266,915– 2.5 51 22q11 duplication M, 37y 3 (basic) 24.7 Self-assessment of moderate anxiety/depression 19,793,730)x3 syndrome 55 arr 22q11(17,504,374– 2.3 47 22q11 duplication F, 26y 4 42.5 Not reported 19,793,730)x3 syndrome (secondary) (Obese class III) 56 arr 22q11(17,512,325– 2.3 46 22q11 duplication M, 19y 2 19.8 Not reported 19,793,730)x3 syndrome (elementary)

Case column: Included are carriers identified in both discovery and replication cohort (n = 7877). Carriers from the replication cohort are marked with (*). Carriers with clinical features formally diagnosed and self-reported that are comparable to those reported in disease cohorts (detailed in eTable2) are emboldened and underlined, respectively. Carriers are listed according to the DECIPHER database “Grading of Microdeletion/Microduplication syndromes” (https://decipher.sanger.ac.uk/disorders#syndromes/overview):. briefly, grade 1 refers to “pathogenic genetic anomalies with high penetrance”; grade 2 to “likely pathogenic anomalies with high penetrance ; Grade 3 to “susceptibility loci with milder phenotypes, and possibly incomplete penetrance”; and ungraded to syndromes only recently identified not yet fully evaluated by DECIPHER.

SNP array results column: The SNP array results are described according to “An International System for Human Cytogenetics Nomenclature (2013)” by Shaffer et al., Karger, Basel 2013. The presented results specify the method used to identify the variant (i.e. “arr” for chromosomal microarrays), the rearranged cytogenetic band, the genomic coordinates of the first and last altered marker (i.e. the CNV breakpoints) and the number of copies within the imbalanced region (e.g. x1 in case of deletion and x3 in case of duplication). Aberration breakpoints are reported as detected using the PennCNV algorithm and are given according to the human genome build 18 (NCBI 36).

Length column: This column indicates the length of the rearrangement in megabases (Mb), i.e. the distance between the genomic coordinates of the first and last altered marker.

Gene column: This column indicates the number of EntrezGene ID genes embedded within each identified imbalanced region, calculated using Ensembl BioMart (NCBI 36, Hg18).

Education column: This column indicates education levels as defined in Methods, briefly: level 1 - less than primary; 2 - primary (currently 3 years); 3 – basic (currently 9 years, includes basic education for children with special needs); 4 – secondary (currently 12 years, includes vocational secondary); 5 – professional higher/college; 6 – university/academic degree; 7 – scientific degree (MSc and PhD).

BMI column: Obesity and underweight are associated to several genomic disorders as specified in eTable 2. The World Health Organization International Classification of adult underweight, overweight and obesity according to BMI (http://apps.who.int/bmi/index.jsp?introPage=intro_3.html) was used to determine obese and underweight carriers of syndromic CNVs.

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Last column: Diagnoses are indicated according to the World Health Organization International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) codes (e.g. F70.1 for mild intellectual disability with significant impairment in behavior). The full list of codes is accessible at the http://apps.who.int/classifications/icd10/browse/2015/en.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 2. Prevalence and characteristic features of DECIPHER-listed genomic disorders

DECIPHER-listed Prevalence Clinical characteristics in Clinical characteristic in References Formatted Table genomic disorders children adults DECIPHER rearrangements graded 1 and 2 1p36 microdeletion 1-2/10,000 Intellectual disability, Improvement in adaptive Ref. 1, 2, 3, syndrome developmental delay; behavior, social 10 hypotonia; feeding interaction and motor difficulties; seizures; skills. Limited cardiac defects; hearing independence and need and vision defects; delayed for lifelong care and cranial suture closure medical support 2q33.1 deletion unknown Intellectual disability; No conclusions available Ref. 1, 2, syndrome significant speech delay; 11 behavioral abnormalities; microcephaly, short stature; a cleft or a high palate; sparse thin hair; ear anomalies 2q37 monosomy 1/100,000 Intellectual disability; Improved communication Ref. 1, 2, 3, autism spectrum disorder; abilities. Limited 4, 12, 13 behavioral abnormalities; independent living, need round face, deep-set eyes, for support in daily duties. thin upper lip; Short adult stature, weight brachydactyly; hypotonia; increase with age, sleep cardiac, gastro-intestinal, disturbancies. genito-urinary defects; Shortened life span, seizures; overweight or congenital malformations obesity being the main factor Phenotypic variability due determining life to the size and location of expectancy the deleted interval Wolf-Hirschhorn 1-9/100,000 Intellectual disability; Phenotype remains Ref. 1, 4, Syndrome microcephaly; hypotonia; similar to that of 14, 15 pre- and postnatal growth childhood. retardation; feeding Average life expectancy difficulties; seizures; of 34 years midline, cardiac, renal, ophthalmic, skeletal defects; distinctive facies with a “Greek-helmet” profile High early-childhood mortality Cri du Chat Syndrome 1-9/100,000 Severe intellectual Severe intellectual Ref. 1, 4, (5p deletion) disability and psychomotor disability, behavioral 16 delay; a high pitched, problems. monotonous (“cat-like”) cry; The craniofacial microcephaly; pre- and appearance becomes post-natal growth less striking with retardation; hypotonia; advancing age. Some distinctive facies with round traits (e.g. long face, face, hypertelorism, broad macrostomia, scoliosis) nasal bridge become more evident Sotos syndrome 1/14,000 Learning difficulties; pre- Depending on the severity Ref. 1, 3, and post-natal overgrowth; of learning disabilities 17, 18 advanced bone age; adult life may vary from cardiac, renal defects; independent to need for distinctive facies with large lifelong support and care. head circumference, Earlier than average age pointed chin; neonatal of menarche. Final height hypotonia and jaundice within the normal range. Adult facial features are more subtle. Williams-Beuren 1/7500 Intellectual disability or Cognitive scores stable Ref. 1, 3, Syndrome learning difficulties with over time; distractibility 19 relative strength in and inattention; anxiety. language and verbal short The mean adult height term memory; distinctive below the 3rd centile. behavioral characteristics Increased frequency of (anxiety, short attention subclinical span, overfriendliness); hypothyroidism, abnormal

Downloaded From: https://jamanetwork.com/ on 09/26/2021 cardiovascular disease oral glucose tests, (aortic valve stenosis, diabetes mellitus. elastin arteriopathy, Accelerated aging, onset hypertension); short of age-related diseases in stature; endocrine, young adulthood. Typical connective tissue appearance with a long abnormalities; distinctive face and neck, sloping facies (“elf-like”) shoulders (“gaunt-like”). Cardiovascular disease the main cause of death. Kleefstra syndrome (9q unknown Severe intellectual Limited independence Ref. 1, 2, 6, subtelomeric deletion) disability, learning and need for lifelong care 20 difficulties; profound and medical support. speech impairment; Progressive regression in hypotonia; microcephaly; behavior, cardiac defects; seizures; neurodegenerative distinctive facies processes in brain structure; disturbed sleep pattern; rigid lexion of limbs, slow motor function; distinctive facies Potocki-Shaffer 1/100,000 Intellectual disability or Variable severity of Ref. 1, 4, syndrome learning disabilities at cognitive disabilities 21, 22, 23, various degree; multiple ranging from normal to exostoses; craniofacial, moderate intellectual opthalmologic defects, disability biparietal formanina; male genital malformations; seizures Angelman syndrome 1/20,000 Severe intellectual Limited independence Ref. 1, 3, 4, disability or learning and need for lifelong care 19, 24 difficulties; profound and medical support speech impairment; Improvement in attention, microcephaly; ataxia; hyperactivity and sleeping seizures with specific EEG problems; less marked abnormalities; facial features due to characteristic behavioral facial coarse-ning. Severe phenotype (jerky epilepsy; dysphagia; movements, frequent ataxic gait; thoracic laughter, a love of water) scoliosis; impaired and a happy, sociable mobility. Sudden deaths disposition; sleep disorder; related to infections, subtle facial dysmorphisms seizures. Prader-Willi syndrome 1/30,000 Intellectual disability, High rate of (morbid) Ref. 1, 3, borderline to low normal obesity; excessive eating; 19 intelligence; behavioral type II diabetes; problems, ritualistic cardiovascular disease; behaviors; central hormonal deficiencies; hypotonia; feeding sleep apnea; gastric difficulties in infancy perforations and necrosis; followed by rapid weight short stature; incomplete gain in early childhood, pubertal development; insatiable appetite, inability infertility to vomit; Complications of obesity hypogonadodrophic major cause of death. hypogonadism; temperature instability; a high pain threshold; ATR-16 syndrome 1/1,000,000 Intellectual disability or No conclusions available Ref. 1, 2, 4 learning difficulties; alpha- thalassemia characterized by microcytosis, hypochromia, normal hemoglobin level or mild anemia; mild nonspecific facial dysmorphisms; club foot; male genital defects Rubinstein-Taybi 1-9/100,000 Intellectual disability; Sudden mood changes Ref. 1, 4, Syndrome behavioral problems; and obsessive- 19, 25 growth retardation, short compulsive behavior stature; microcephaly; becomes gradually more broad thumbs and frequent. Cardiac, halluces; gastrointestinal gastrointestinal, renal problems; feeding disease An increased risk difficulties; respiratory of tumors, leukemia,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 infections; distinctive lymphoma; immune facies; an increased risk of dysfunction leukemia 17q21.31 recurrent 1/16,000 Intellectual disability; Limited independence Ref. 1, 2, 5 microdeletion syndrome oromotor dyspraxia; and need for lifelong care friendly/amiable behavior; and medical support low birth weight, hypotonia, Coarsening of facial feeding difficulties in features with age. infancy Charcot-Marie-Tooth 1/2500 Demylleinating peripheral Clinically normal adults Ref. 1, 5, 6, syndrome type 1A neuropathy; difficulty are rare, but exist; the 26, 27 walking present at the age degree of disability varies. 5-15y; distal muscle Increased trend towards weakness and atrophy; pes depression, a high risk of cavus reduced quality of life, Age-dependent penetrance sleep impairment. and variable expressivity Life expectancy is normal in most patients Hereditary Liability to 2-5/100,000 History of recurrent focal Symptomes vary in Ref. 1, 5 Pressure Palsies pressure nerve palsies, severity (from subclinical carpal tunnel syndrome; to prolonged disability). pes cavus Life expectancy is normal Miller-Dieker syndrome 1/100,000 Severe intellectual Severe mental handicap, Ref. 1, 4, 5 disability; lissencephaly; reduced life span (most microcephaly; epilepsy; patients do not survive cardiac defects; beyond childhood) omphalocele; joint contractures; feeding problems; life-threatening breathing problems; dysmorphic features NF1-microdeletion 1/3000 Neurofibromas, Lisch Many features of NF Ref. 1, 3, syndrome noduls in the iris, café-au- increase in frequency with 28 lait spots; increased risk of age; prognosis is worse malignancies; cardiac for females defects; intellectual disability or learning difficulties; coarse facies Very variable expressivity, many traits have age- dependent penetrance Smith-Magenis 1/15,000 Intellectual disability or Behavioral problems Ref. 1, 3, 5, Syndrome learning difficulties; continue to change until 19, 29, 30 behavioral problems adulthood (inattention, (maladaptation, self- distractibility, injurious, stereotypic aggressiveness, self- behaviors); obesity; sleep injurious); inverted disorder, general lethargy; circadian rhythm of hypotonia; distinctive (flat, melatonin, sleep square, heavy) facies; disturbances; elevated cholesterol, triglycerides; ocular problems; hearing loss; velopharyngeal insufficiency; self-injury; peripheral neuropathy 22q11 1/4000 Cardiac and palatal The prognosis is variable Ref. 1, 2, 3, deletion/Velocardiofacial defects; learning and depends on the 4, 5, 31 / DiGeorge syndrome difficulties, delayed speech severity of the disease. and language Higher risk for psychiatric development; immune illnesses (bipolar disorder, deficiency, an elevated risk psychosis, to develop autoimmune schizophrenia). disease; transient neonatal Mortality in adults is hypocalcemia; nasal higher that that of the speech; distinctive facies general adult population Phelan-McDermid 1/14,000 Intellectual disability; Speech remains impaired Ref. 1, 2, 3, syndrome (22q13 severe expressive throughout life, need for 33, 34 deletion) language delay; autism special training and spectrum disorder; support. Development of behavioral problems lymphoedema, cellulitis (hyperactivity, during teenage and adult aggressiveness); age. Most adults fall in decreased sensitivity to normal height and weight pain; hypotonia; range. overgrowth; subtle and No life-threatening

Downloaded From: https://jamanetwork.com/ on 09/26/2021 variable facial features problesm, life expectancy is normal

Prevalence of grade 1 21/10,000 and 2 DECIPHER syndromes

DECIPHER rearrangements graded 3 and ungraded 1q21.1 recurrent 1/1900 Highly variable phenotype, High intra- and inter- Ref. 1, 2, 4, microdeletion ranging from familial phenotypic 32, 35 asymptomatic/normal diversity, incomplete cognitive functioning to penetrance and lack of severe developmental distinctive features makes delay and congenital genetic counseling anomalies (cardiac, problematic. ophthalmic defects); No conclusions available microcephaly; increased risk of behavioral and psychiatric problems. Best regarded as a susceptibility locus than a clinically distinctive syndrome. 1q21.1 recurrent 1/4000 Highly variable phenotype, High intra- and inter- Ref. 1, 9, microduplication ranging from familial phenotypic 32 asymptomatic/normal diversity, incomplete cognitive functioning to penetrance and lack of severe developmental distinctive features makes delay and congenital genetic counseling anomalies; autistic problematic. behaviors; No conclusions available macrocephaly/relative macrocephaly Best regarded as a susceptibility locus than a clinically distinctive syndrome. 1q21.1 susceptibility 1/4000 Susceptibility factor for Susceptibility factor for Ref. 1, 9, locus for TAR syndrome thrombocytopenia-absent TAR syndrome 32 radius (TAR) syndrome 2p15-16.1 microdeletion 1/100,000 Moderate to severe No conclusions available Ref. 1, 2, 4, syndrome intellectual disability; 36 feeding problems in infancy; microcephaly; vision problems (optic nerve hypoplasia); urogenital defects; facial dysmorphisms 2p21 Microdeletion 1/100,000,000 Developmental delay; No conclusions available Ref. 1, 4, 6, Syndrome hypotonia; cystinuria; 37, 38 growth delay, followed by hypephagia and rapid weight gain in late childhood in some cases; neonatal seizures; lactic academia; tendency towards late puberty, hypergonadotropic hypogonadism, minor facial dysmorphisms 3q29 microdeletion unknown Highly variable phenotype, The prognosis is variable Ref. 1, 2, syndrome cognitive skills range from and depends on the 39, 40 normal cognition to severity of the disease. intellectual disability; Psychiatric problems speech delay; (schizophrenia) microcephaly; autism Likely normal life spectrum disorder; motor expectancy delay; subtle distinctive facies 3q29 microduplication unknown Highly variable phenotype, Highly variable Ref. 1, 2 syndrome cognitive skills range from phenotype, no normal cognition, learning conclusions available problems or intellectual disability; microcephaly;

Downloaded From: https://jamanetwork.com/ on 09/26/2021 speech delay; possible tendency to overweight Best regarded as a susceptibility locus than a clinically distinctive syndrome. Adult-onset autosomal unknown No conclusions available Slow progression of Ref. 1, 41 dominant widespread symmetrical leukodystrophy myelin loss in the central nervous system; abnormality of pyramidal motor function, dysautonomia, leukodystrophy Highly penetrant, onset of symptoms usually at the age of 30-40 years Familial Adenomatous 1/7000 Onset of precancerous Predisposition to colon Ref. 1, 3, 5 Polyposis colonic polyps on average neoplasms. Presence of at the age of 16 years polyps by age 35 years in 95% of individuals, cancer is inevitable without colectomy (the mean age of diagnosis in untreated individuals is 39 years) 7q11.23 duplication 1/13,000 Severe speech and The prognosis is variable Ref. 1, 2, syndrome language delay; cognitive and depends on the 39, 42, 43, functioning ranges from the severity of the disease. 44, 45, 46 normal range to moderate Many face speech and intellectual social challenges; disability/learning language delay and difficulties; behavioral learning difficulties may problems; autism spectrum resolve in later life. disorder; aortic dilation; Predisposition to subtle distinctive facial schizophrenia features Variable phenotype Split hand/foot 1-9/100,000 Heterogeneous distal limb Heterogeneous distal limb Ref. 1, 4 malformation 1 defects with a wide range defects with a wide range of severity; hypoplasia or of severity. absence of central rays of the hand and feet, median clefts of the hand and feet, syndactyly; hearing loss; urogenital defects; cleft palate, median cleft lip 8p23.1 deletion unknown Intellectual disability, The prognosis is variable, Ref. 1, 2, 4, syndrome developmental delay; some individuals with 47, 48 congenital complex cardiac normal intelligence have defects, atrioventricular been reported, learning canal, spetal defects, difficulties may resolve in pulmonary stenosis are later life allowing normal common; characteristic independent life; behavioral profile behavioral problems. (hyperactivity, Cardiac anomalies is the impulsiveness); congenital most significant medical diaphragmatic hernia; concern that affect can limited reports about early lifespan puberty Mortality in infancy due to severe cardiac defects or respiratory distress in some cases 8p23.1 duplication 1/1,000,000 Intellectual disability, Compatible with Ref. 1, 2, 4, syndrome learning difficulties; speech independent adult life with 49, 50 delay; congenital cardiac variable degree of support defects; behavioral problems, attention deficit hyperactivity disorder; neonatal respiratory stress; balance problems; hypotonia; cleft lip and palate; subtle facial dysmorphisms

Downloaded From: https://jamanetwork.com/ on 09/26/2021 8q21.11 Microdeletion 1/1,000,000 Intellectual disability; No conclusions available Ref. 1, 4, 6, Syndrome unusual behavior; finger 51 and toe defects; hypotonia; hearing impairment; corpus callosum agenesis; distinctive facies WAGR 11p13 deletion 1/500,000 Intellectual disability; Lifelong risk of renal Ref. 1, 3, 5 syndrome behavioral abnormalities; dysfunction; aniridia; genital defects and opthalmological problems disorders; increased risk of in adolescents and adults. Wilms tumor; obesity 12p13.33 Microdeletion 1/1,000,000 Developmental delay; No conclusions available Ref. 1, 4, Syndrome speech disorder; 52, 53 behavioral problems 12q14 microdeletion 1/1,000,000 Intellectual disability, Adult carriers may have Ref. 1, 2, 4, syndrome developmental delay; learning difficulties; 54, 55 speech delay; failure to reduced adult height thrive; growth retardation; osteopoikilosis; cardiac defects; subtle facial dysmorphisms 15q13.3 microdeletion 1/2500 Intellectual disability, Limited information about Ref. 1, 2, 3, syndrome learning problems; adolescent and adult 56, 57 seizures; speech problems; phenotypes. behavioral problems; The prognosis is variable autism spectrum disorder; and depends on the schizophrenia; subtle facial severity of the disease. dysmorphisms Compatible with Neuropsychiatric problems independent adult life in in 80% of carriers. Major many cases since congenital malformations 15q13.3 deletions are are uncommon typically (85%) inherited 15q24 recurrent 1/25,000 Intellectual disability; pre- No conclusions available. Ref. 1, 3, 4, microdeletion syndrome and post-natal growth May cause reduced 58 retardation; microcephaly; fertility. genital, skeletal, digital defects; hypospadias; loose connective tissue; distinctive facies Extent and severity of feature vary between individuals 15q26 overgrowth unknown Intellectual disability; tall Tall adult height; no Ref. 1, 59, syndrome stature; macrocephaly; conclusions on cognitive 60 renal defects; distinctive and behavioral problems facies 16p11.2 1/2,000 Highly variable phenotype, The prognosis is variable Ref. 1, 2, microduplication cognitive skills range from and depends on the 39, 61, 62, syndrome normal cognition, learning severity of the disease. 64, 65 problems or intellectual Increased risk for disability; neuropsychiatric psychiatric problems, problems; risk for being schizophrenia, psychosis, underweight; reduced head depressive disorder size; Rolandic epilepsy; congenital defects in some cases; structural changes in brain 16p11.2 microdeletion 1/2,000 Highly variable phenotype, The prognosis is variable Ref. 1, 2, 4, syndrome cognitive skills range from and depends on the 61, 66, 67, normal cognition, learning severity of the disease. 68, 69, 70, problems or intellectual High-penetrant extreme 71, 72, 73, disability; speech and obesity, incread risk for 74, 75 language delay, childhood related diseases (Type II apraxia; autism spectrum diabetes, metabolic disorder; age-dependent syndrome); (female) obesity, disturbed apetite genital tract defects may and satiety; macrocephaly; reduce fertility epilepsy, paroxysmal neurologic problems; urogenital defects, Müllerian duct anomalies; vertebral defects, congenital scoliosis; structural changes in brain

Downloaded From: https://jamanetwork.com/ on 09/26/2021 16p11.2-p12.2 unknown Intellectual disability; No conclusions available Ref. 1, 6, microdeletion syndrome speech delay; behavioral 76, 77, 78 problems, attention deficit; feeding difficulties in infancy; short stature; hypotonia; recurrent ear infections; congenital defects, eye defects, cardiac defects, orofacial clefting; distinctive facies 16p13.11 recurrent 1/2800 Neurocognitive disorder Many have no Ref. 1, 2, 9, microdeletion susceptibility locus. developmental delay or 79, 80, 81 Intellectual functioning is health issues, carriers highly variable, many may have experienced carriers have normal learning difficulties in cognition, may cause childhood/adolescence; a developmental delay, risk factor for neurological learning difficulties; conditions and psychiatric increased risk for disturbancies, obsessive- seizures/epilepsy, compulsive disorder, congenital defects of schizophrenia various organs, microcephaly; constipation; vision problems 16p13.11 recurrent 1/400 Neurocognitive disorder Many have no Ref. 1, 2, microduplication susceptibility locus. developmental delay or 56, 82, 83, Intellectual functioning is health issues, carriers 84, 85 highly variable, many may have experienced carriers have normal learning difficulties in cognition, may cause childhood/adolescence; a learning difficulties, risk factor for neurological intellectual disability; conditions and psychiatric incread risk for seizures, disturbancies autism spectrum disorder, behavioral problems, congenital defects of various organs; vision problems Potocki-Lupski 1/ 20,000 Variable cognitive No conclusions available Ref. 1, 2, 7, syndrome (17p11.2 functioning, ranges from 86 duplication) borderline normal to intellectual disability; speech delay; behavioral problems; hyperactivity, attention deficit; autism spectrum disorder; feeding difficulties, failure to thrive, short stature; hypotonia; sleep apnea; passiveness; cardiac defects; subtle distinctive facies RCAD (renal cysts and 1/4300 A wide clinical spectrum; Diabetes mellitus Ref. 1, 4, 9, diabetes) renal defects present diagnosed usually 87 usually in early life; genital between 10 and 40 years anomalies; diabetes of age. mellitus; liver defects; Half of the patients have pancreatic atrophy; impaired renal function, hyperuricaemia; gout; risk around 12% end-stage for autism spectrum renal failure disorder and schizophrenia Early-onset Alzheimer 1-9/100,000 No conclusions available Progressive dementia of Ref. 1, 4 disease with cerebral Alzheimer disease with a amyloid angiopathy mean age of onset of 52 years; typical neuropathological findings of Alzheimer disease 22q11 duplication 1/4000 Clinical presentations are Prognosis is variable due Ref. 1, 2, 4, syndrome extremely variable, ranging to intra- and inter-familial 8, 88, 89, from generally mild variability. 90 learning difficulties with a Compatible with subset of individuals being independent adult life in essentially normal to many cases since 22q11 intellectual duplications are often disability/multiple defects. (70%) inherited. Congenital defects may May be a protective factor

Downloaded From: https://jamanetwork.com/ on 09/26/2021 overlap with the reciprocal against schizophrenia 22q11 deletion/Velocardiofacial syndrome; significant cardiovascular defects may lead to early death 22q11.2 distal deletion unknown Variable severity of clinical Prognosis is variable due Ref. 1, 2, 6, syndrome features, ranging from to intra- and inter-familial 91, 92 unaffected to severe variability. features. Cognitive function Compatible with vary from normal to independent adult life in learning difficulties, many cases, unaffected intellectual disability; carrier parents have been speech, articulation recurrently identified problems; behavioral difficulties; prematurity; pre- and post-natal growth retardation; diverse congenital defects, cardiac defects are common; distinctive facies Cat-Eye Syndrome 1-9/100,000 Considerable intra- and The prognosis depends Ref. 1, 4, 6 (Type I) inter-familial variability; on the severity of intellectual abilities vary malformations and from normal range to cognitive functioning. varying degree of Life expectancy is not intellectual disability; ocular significantly reduced for coloboma (“cat-eye”); anal patients with few or mild atresia; preauricular manifestations defects; congenital defects, cardiac defects; micrognathia; short stature; distinctive facies Severe multiple malformations can be life- threatening in infancy

Prevalence of grade 3 64/10,000 and ungraded DECIPHER syndromes

Prevalence of 85/10,000 DECIPHER syndromes

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 3. Sample demographics and characteristics Cohort Study Ethnicity Number Cohort type Mean Female Education of age (%) measure individuals (years ± SD) EGCUT Estonian Estonian 6819 General 49.9 ± 51.3 Highest (discovery) population population 19.3 achieved biobank education level EGCUT Estonian Estonian 1058 General 43.8 ± 50.3 Highest (replication) population population 16.3 achieved biobank education level EGCUT Estonian Estonian 993 General 37.7 ± 51.6 Highest (“higher- population population 15.8 achieved functioning”) biobank education level HYPERGENES Hypertension Italian 451 Control cohort 59.0 ± 55.2 Highest study 4.4 achieved education level MCTFR Minnesota European 2390 General 21.5 ± 54.2 Full scale IQ Center for Twin American population 13.6 and Family (enriched for Research twins) studies ALSPAC Avon British 5218 Birth cohort 14.1 ± 53.9 Standard Longitudinal (5160 0.32 Assessment Study of Maths and Test scores Parents and 5022 (SATs) Children English

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 4. Summary scores of ALSPAC participants Standard Assessment Tests (SATs) Population Tertile Maths English Median IQR N (%) Median IQR N All ALSPAC 1 4.83 4.24, 3567 4.85 4.23, 3467 participants 5.30 (33.53%) 5.14 (33.73%) with available 2 6.24 6.05, 3527 5.71 5.57, 3617 data 6.53 (33.15%) 5.95 (35.19%) 3 7.46 7.17, 3545 6.65 6.41, 3195 8.00 (33.32%) 7.06 (31.08%) Total 6.23 5.30, 10679 5.70 5.14, 10279 7.17 (100%) 6.35 (100%) ALSPAC 1 4.89 4.33, 1448 4.85 4.29, 1429 participants 5.37 (28.06%) 5.14 (28.45%) analyzed in 2 6.25 6.05, 1767 5.74 5.57, 1815 this study 6.56 (34.24%) 5.95 (36.14%) 3 7.5 7.19, 1945 6.71 6.41, 1778 8 (37.69%) 7.06 (35.40%) Total 6.39 5.58, 5160 5.81 5.29, 5022 7.29 (100%) 6.47 (100%) Summary statistics for Mathematics and English SATs scores (scaled and adjusted, but not further transformed), according to tertile (1=lowest educational achievement, 3=highest). Tertiles were generated using all ALSPAC participants with available data. Summary statistics for tertiles in the broader ALSPAC population, as well as the summary statistics for those included in this particular study are given. Since some participants have exactly equivalent scores, the numbers generated for each tertile are not equal. Abbrevations: IQR:interquartile range; N:number in tertile.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 5. Prevalence of NAHR-mediated recurrent CNVs in clinical and general population cohorts Syndrome DECIPHE Chromoso Approximate Number of Number of Number of R me locus coordinates carriers carriers carriers grade (Hg18/NCBI36 (prevalenc (prevalenc (prevalenc ) e) in the e) in the e) in the Dittwald et Kaminsky EGCUT al. 2013 et al. 2011 cohort cohort cohort n=7877 n=25,144 n=15,749 (this work) (Ref.1) (Ref.2) Thrombocytopenia- Grade 3 1q21 chr1:14409786 16 (1 in 17 (1 in 4 (1 in absent radius 3-144459424 1,572) 926) 1,969) syndrome (TAR) Reciprocal duplication Not listed 1q21 chr1:14409786 28 (1 in 9 (1 in 3 (1 in to TAR-region 3-144459424 898) 1,750) 2,625) 1q21.1 deletion Grade 3 1q21.1 chr1:14500000 41 (1 in 55 (1 in 3 (1 in syndrome 0-146350000 613) 286) 2,625) 1q21.1 duplication Grade 3 1q21.1 chr1:14500000 39 (1 in 28 (1 in 6 (1 in syndrome 0-146350000 645) 562) 1,313) 3q29 deletion Ungraded 3q29 chr3:19721123 18 (1 in 9 (1 in 0 syndrome 2-198829060 1,397) 1,750) (unknown) 3q29 duplication Ungraded 3q29 chr3:19721123 11 (1 in 8 (1 in 1 (1 in syndrome 2-198829060 2,286) 1,969) 7,877) Sotos syndrome Grade 1 5q35 chr5:17565724 3 (1 in 8 (1 in 0 2-176984722 8,381) 1,969) (unknown) 5q35 duplication Not listed 5q35 chr5:17565724 3 (1 in 2 (1 in 0 2-176984722 8,381) 7,875) (unknown) Williams-Beuren Grade 1 7q11.23 chr7:72382391 56 (1 in 34 (1 in 1 (1 in syndrome (WBS) -73780608 449) 463) 7,877) 7q11.23 duplication Ungraded 7q11.23 chr7:72382391 13 (1 in 16 (1 in 1 (1 in syndrome -73780608 1,934) 984) 7,877) 8p23.1 deletion Ungraded 8p23.1 chr8:8137465- 13 (1 in 10 (1 in 1 (1 in 11802038 1,934) 1,575) 7,877) 8p23.1 duplication Ungraded 8p23.1 chr8:8137465- 3 (1 in 6 (1 in 0 11802038 8,381) 2,625) (unknown) Prader-Willi Grade 1 15q11.2q12 chr15:2130948 39 (1 in 41 (1 in 0 syndrome/Angelman 3-26230781 645) 384) (unknown) syndrome (PWS/AS) BP2-BP3 15q11.2q13 BP2-BP3 Not listed 15q11.2q12 chr15:2130948 11 (1 in 35 (1 in 0 duplication 3-26230781 2,286) 450) (unknown) 15q13.3 deletion Ungraded 15q13.3 chr15:2892439 53 (1 in 46 (1 in 2 (1 in syndrome BP4 BP5 6-30232700 474) 342) 3,939) 15q13.3 duplication Not listed 15q13.3 chr15:2892439 25 (1 in 14 (1 in 2 (1 in syndrome BP4 BP5 6-30232700 1,006) 1,125) 3,939) 16p13.11 deletion Ungraded 16p13.11 chr16:1540054 41 (1 in 22 (1 in 2 (1 in syndromes (1.5Mb & 7-18513898 613) 716) 3,939) 3Mb) 16p13.11 duplication Ungraded 16p13.11 chr16:1540054 81 (1 in 45 (1 in 14 (1 in syndromes (1.5Mb & 7-18513898 310) 350) 563) 3Mb) 16p11.2 deletion Ungraded 16p11.2 chr16: 87 (1 in 67 (1 in 4 (1 in syndrome BP4-BP5 29,557,497- 289) 235) 1,970) 30,107,356 16p11.2 duplication Ungraded 16p11.2 chr16: 66 (1 in 39 (1 in 7 (1 in syndrome BP4-BP5 29,557,497- 381) 404) 1,125) 30,107,356 Charcot-Marie-Tooth Grade 1 17p12 chr17:1403864 17 (1 in NA 3 (1 in disease, demyelinating, 0-15411628 1,479) 2,625) type 1A (CMT1A) Hereditary Neuropathy Grade 1 17p12 chr17:1403864 14 (1 in NA 2 (1 in with Liability to 0-15411628 1,796) 3,939) Pressure Palsies Smith-Magenis Grade 1 17p11.2 chr17:1671379 9 (1 in 16 (1 in 0 syndrome 7-20162741 2,794) 984) (unknown) Potocki-Lupski Ungraded 17p11.2 chr17:1671379 11 (1 in 15 (1 in 0 syndrome 7-20162741 2,286) 1,050) (unknown) Renal cysts and Ungraded 17q12 chr17:3188918 15 (1 in 18 (1 in 0 diabetes syndrome 5-33290030 1,676) 875) (unknown) (RCAD) 17q12 duplication Not listed 17q12 chr17:3188918 25 (1 in 21 (1 in 7 (1 in 5-33290030 1,006) 750) 1,125)

Downloaded From: https://jamanetwork.com/ on 09/26/2021 17q21.31 deletion Grade 1 17q21.31 chr17:4106094 14 (1 in 22(1 in 0 syndromes (Koolen-de 9-41650183 1,796) 716) (unknown) Vries syndrome) 17q21.31 duplication Not listed 17q21.31 chr17:4106094 0 0 0 syndromes 9-41650183 (unknown) (unknown) (unknown) 22q11.2 deletion Ungraded 22q11.2 chr22:2024711 2 (1 in NA 0 syndrome, distal 7-22052445 12,575) (unknown) 22q11.2 duplication Not listed 22q11.2 chr22:2024711 3 (1 in NA 0 syndrome, distal 7-22052445 8,381) (unknown) DiGeorge Grade 1 22q11.2 chr22:1738979 183 (1 in 93 (1 in 0 syndrome/Velocardiofa 2-19782445 137) 169) (unknown) cial syndrome (DGS/VCFS) DECIPHER grade: see footnote of eTable 2 for grading details. References: (1) Dittwald P et al. Genome Res. 2013 Sep;23(9):1395-409. doi: 10.1101/gr.152454.112; (2) Kaminsky EB et al. Genet Med. 2011 Sep;13(9):777-84. doi: 10.1097/GIM.0b013e31822c79f9.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 6. Follow-up phenotyping of 16p11.2 600kb BP4-BP5 deletions and duplications identified in the EGCUT cohort.

Ca 16p1 Gend Educatio FSI VI PI BM BM Profession Additional Formatted Table se 1.2 er, n Q Q Q I-I3 I-II4 remarks to the Age1 initial phenotype from follow-up investigations 41* DEL M, 3 (basic) 91 N 99 35. 51. Manufactur G47.3-3 33y A 9 9 ing, (obstructive warehouse sleep apnea); officer R56.8 (unspecified convulsions)R 47.1 (dysarthria); I19 (hypertensive disease) 42 DEL F, 4 95 N 95 37. 43. Accoutant E11 (Diabetes 55y (seconda A 2 8 mellitus type ry) 2); L40.5(arthrop atic psioriasis) 43 DEL M, 3 (basic) NA N N 30. NA Crane, NA NA A A 1 hoist and related plant operator 44 DEL F, 3 (basic) 87 80 90 34. 35. Mail carrier F32.1 41y 9 2 (3y), (moderate currently depressive on episode); maternity F80.0 (specific leave with articulation her 16 disturbance); months old K07.2 son (in (anomalies of vitro fertili- dental arch zation relationship); pregnancy) L68.0 (hirsutism); O10 (hypertension complicated pregnancy); O82.0 (pre- planned caesarian section); Q52 (septate vagina); Q67.4 (congenital deformities of skull, face and jaw); irregular menstruation; self-

Downloaded From: https://jamanetwork.com/ on 09/26/2021 assessment of moderate problems with daily duties; language and learning difficulties at school 45* DUP F, 3 (basic) 42 58 60 19. 18. Baby-sitter F33.1 32y 1 6 (1y), (recurrent currently depressive disability disorder, pensioneer moderate); F41.2 (anxiety disorder with depression); F79 (mental retardation, unspecified); Q70.1 (partial syndactyly); irregular menstruation; self assessment of severe anxiety/depres sion and moderate problems with daily duties; learning and behavioral problems at school 46* DUP F, 3 (basic) 94 80 87 17. 23. Cook (1y), Self- 30y 6 7 currently assessment of on moderate maternity anxiety/depres leave with sion; K07.3 her 7 (anomalies of months old teeth son position); O14.1 (severe pre- eclampsia), O45.9 (premature separation of placenta); O82.1 (emergency caesarean section); O03 (spontaneous abortion) 47 DUP M, 3 (basic)2 114 11 90 25. 25. Lock smith Not reported 65y 6 8 5 (13y), truck driver (33y)

Downloaded From: https://jamanetwork.com/ on 09/26/2021 48 DUP F, NA 2 NA N N 22. NA NA Deceased at (element A A 7 the age of 78y ary) (malignant neoplasm of uterus) 49 DUP M, 4 NA N N 24. NA Building NA NA (seconda A A 2 frame ry) worker 50 DUP F, 4 86 90 11 18. 18. Sales O14 (pre- 43y (seconda 8 8 4 person eclampsia); ry) (18y), O82.1 currently (emergency on caesarean maternity section); O03 leave with (spontaneous her 11 abortion); months old irregular daughter menstruation; self assessment of moderate anxiety/depres sion; 51 DUP M, 6 NA N N 26. NA Philologist, Deceased at NA (universit A A 0 translator the age of 68y y degree) (traffic accident)

The carriers of 16p11.2 600kb BP4-BP5 rearrangements identified in either the discovery or the replication cohort are included (total nb of individuals screened = 7877). Carriers from the replication cohort are marked with (*). Specifications are described in details in the footnote of eTable 1. Likewise case number, as well as details from molecular studies (e.g. aberration breakpoints) and initial EGCUT questionnaire are provided in eTable1 and not repeated here. Diagnoses made during the follow-up study are indicated according to the World Health Organization International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) codes.

1Age at the time of follow-up investigations, if available. 2The initially scored secondary education (eTable1) was corrected to basic during the follow-up investigations. 3 BMI-I: BMI measured upon enrolment to EGCUT 4BMI-II: BMI measured during follow-up investigations, if available Abbreviations: DEL: deletion; DUP: duplication; FSIQ: Full Scale Intelligence Quotient; VIQ: Verbal IQ; PIQ: Performance IQ; NA: not available

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 7. Individual CNVs in EGCUT discovery and replication cohorts A. List of individual deletion regions Chromosome Start Position (Hg18) End Position (Hg18) Size (bp) CNV 1 758 311 1 429 533 671 222 1 1 2 348 804 2 717 664 368 860 1 1 21 091 861 21 400 218 308 357 1 1 28 105 709 28 390 596 284 887 1 1 76 884 639 77 265 277 380 638 1 1 79 449 615 79 848 408 398 793 1 1 97 456 254 97 735 623 279 369 1 1 144 106 312 144 474 316 368 004 1 1 144 109 304 144 458 820 349 516 1 1 144 337 336 144 519 174 181 839 1 1 144 337 336 144 519 174 181 839 1 1 144 800 611 146 325 568 1 524 957 1 1 144 800 611 146 325 568 1 524 957 1 1 144 967 972 146 325 568 1 357 596 1 1 169 301 421 169 665 549 364 128 1 1 172 476 601 172 894 321 417 720 1 1 172 636 390 172 894 321 257 931 1 1 186 679 782 187 213 302 533 520 1 1 207 074 401 207 429 639 355 238 1 1 227 126 923 227 542 233 415 310 1 1 229 791 873 230 216 465 424 592 1 1 246 493 107 246 868 624 375 517 1 2 14 230 313 14 518 805 288 492 1 2 21 267 647 21 978 872 711 225 1 2 24 473 387 25 774 758 1 301 371 1 2 34 405 070 34 683 909 278 839 1 2 34 405 070 34 683 909 278 839 1 2 34 564 586 34 821 990 257 404 1 2 35 057 672 35 463 619 405 947 1 2 49 670 038 49 927 946 257 908 1 2 50 640 323 51 047 358 407 035 1 2 51 324 825 51 610 616 285 791 1 2 51 337 031 51 606 865 269 834 1 2 51 337 031 51 606 865 269 834 1 2 51 337 031 51 606 865 269 834 1 2 52 315 243 52 651 343 336 100 1 2 66 062 989 66 334 021 271 032 1 2 74 814 524 78 511 788 3 697 264 1 2 97 078 050 97 390 976 312 926 1 2 97 097 545 97 390 976 293 431 1 2 97 097 545 97 390 976 293 431 1 2 97 097 545 97 390 976 293 431 1 2 105 056 568 106 621 984 1 565 416 1 2 105 056 568 106 621 984 1 565 417 1 2 111 108 728 112 811 264 1 702 536 1 2 114 353 701 114 834 542 480 841 1 2 131 196 881 131 668 431 471 550 1 2 155 089 577 155 758 262 668 685 1 2 177 117 393 177 560 537 443 144 1 2 180 631 925 180 889 175 257 250 1 2 184 232 832 184 665 411 432 579 1 2 186 378 349 186 679 840 301 491 1 2 195 156 637 196 083 765 927 128 1 2 213 843 955 214 926 902 1 082 947 1 2 219 746 561 220 200 242 453 681 1

Downloaded From: https://jamanetwork.com/ on 09/26/2021 2 240 854 701 242 593 982 1 739 281 1 2 177120045 177582562 462 517 1 2 35671611 35941146 269 535 1 2 195170040 195675318 505 278 1 3 36 495 2 796 443 2 759 948 1 3 668 832 1 036 877 368 045 1 3 2 208 338 2 503 999 295 661 1 3 2 806 511 3 947 118 1 140 607 1 3 4 139 486 4 395 713 256 227 1 3 7 338 887 7 723 843 384 956 1 3 19 628 391 19 923 057 294 666 1 3 28 834 860 29 114 551 279 691 1 3 50 137 295 50 392 019 254 724 1 3 75 489 835 75 820 822 330 987 1 3 83 075 971 83 398 721 322 750 1 3 97 270 450 97 556 275 285 825 1 3 109 547 714 109 806 723 259 009 1 3 116 223 690 116 650 801 427 111 1 3 146 960 115 147 235 163 275 048 1 3 193 379 911 193 649 842 269 931 1 3 1659810 2175851 516 041 1 3 104935423 105295116 359 693 1 4 14 904 203 15 195 323 291 120 1 4 30 949 108 32 051 858 1 102 750 1 4 63 446 357 64 172 520 726 163 1 4 86 752 956 87 099 697 346 741 1 4 90 590 802 91 000 284 409 482 1 4 116 651 869 116 989 195 337 326 1 4 135 817 909 136 483 157 665 248 1 4 137 899 522 138 247 146 347 624 1 4 139 224 988 139 628 741 403 753 1 4 160 747 055 161 028 817 281 762 1 4 164 760 251 166 578 870 1 818 619 1 4 179 703 677 183 972 303 4 268 626 1 4 180 679 295 181 603 283 923 988 1 4 188 807 197 189 338 767 531 570 1 4 188 898 937 189 522 110 623 173 1 4 190 270 460 191 200 760 930 300 1 4 190 704 117 191 176 659 472 542 1 4 172232807 177268919 5 036 112 1 4 139196255 139636948 440 693 1 4 188698152 190207936 1 509 785 1 5 22 700 474 22 977 425 276 951 1 5 35 280 609 35 941 991 661 382 1 5 35 285 179 35 934 633 649 454 1 5 35 285 179 35 934 633 649 454 1 5 62 266 047 62 896 682 630 635 1 5 84 846 031 85 173 074 327 043 1 5 89 719 620 90 009 377 289 757 1 5 95 449 579 95 877 449 427 870 1 5 99 506 327 100 173 897 667 570 1 5 120 237 599 120 505 844 268 245 1 5 120 247 239 120 505 844 258 605 1 5 175 201 098 175 617 567 416 469 1 5 35298975 35940968 641 993 1 5 25747485 26100560 353 075 1 6 43 144 618 43 434 222 289 604 1 6 58 276 111 58 860 048 583 938 1

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 10 41 756 307 42 147 957 391 650 1 10 41 756 307 42 147 957 391 650 1 10 41 756 307 42 147 957 391 650 1 10 46 832 594 47 173 875 341 281 1 10 55 953 160 56 461 965 508 805 1 10 66 524 298 66 805 767 281 469 1 10 66 524 298 66 805 767 281 469 1 10 66 877 815 67 132 299 254 484 1 10 75 517 810 76 004 550 486 740 1 10 81 642 246 81 964 793 322 547 1 10 81 660 394 81 964 793 304 399 1 10 134 671 412 134 971 721 300 309 1 10 134 696 972 134 948 819 251 847 1 10 55956562 56433592 477 030 1 11 280 158 549 963 269 805 1 11 25 106 667 25 556 562 449 895 1 11 50 403 887 51 078 593 674 706 1 11 84 358 039 84 795 179 437 140 1 11 88 984 050 89 483 213 499 163 1 11 93 952 878 94 258 099 305 221 1 11 93 952 878 94 258 099 305 221 1 11 132 491 583 132 779 122 287 539 1 12 15 875 378 16 132 922 257 544 1 12 20 898 985 21 303 121 404 136 1 12 20 898 985 21 303 121 404 136 1 12 20 898 985 21 303 121 404 136 1 12 36 162 667 36 441 465 278 798 1 12 61 865 335 62 202 949 337 614 1 12 65 273 019 65 693 922 420 903 1 12 85 702 102 86 164 764 462 662 1 12 125 711 113 126 075 206 364 093 1 12 130 384 373 130 663 885 279 512 1 12 130 384 373 130 663 885 279 512 1 12 130 384 373 130 663 885 279 512 1 12 125712851 126074584 361 733 1 12 76241599 76705203 463 604 1 12 130398112 130658558 260 446 1 13 23 118 816 23 388 921 270 105 1 13 23 118 816 23 388 921 270 105 1 13 34 578 457 34 878 005 299 548 1 13 49 341 679 49 596 154 254 475 1 13 62 367 339 62 840 015 472 676 1 13 104 137 827 104 663 264 525 437 1 13 108 986 242 114 121 631 5 135 389 1 13 102637939 102917124 279 185 1 14 21 637 401 22 034 622 397 221 1 14 41 516 716 42 180 851 664 135 1 14 60 223 547 60 479 792 256 245 1 14 97 911 433 99 522 413 1 610 980 1 14 104 176 814 105 118 950 942 136 1 14 104 217 623 105 270 624 1 053 002 1 15 19 157 192 19 408 394 251 202 1 15 20 229 762 20 665 815 436 053 1 15 21 908 305 22 219 100 310 795 1 15 21 920 736 22 219 100 298 364 1 15 21 927 715 22 219 100 291 385 1 15 24 376 622 25 115 126 738 504 1 15 24 443 629 26 208 861 1 765 232 1

Downloaded From: https://jamanetwork.com/ on 09/26/2021 15 24 443 629 26 208 861 1 765 232 1 15 24 469 262 26 208 861 1 739 599 1 15 26 761 172 28 159 066 1 397 894 1 15 26 798 209 28 159 066 1 360 857 1 15 28 686 425 30 301 633 1 615 209 1 15 28 750 112 30 301 633 1 551 522 1 15 49 852 924 50 138 955 286 031 1 15 21927715 22666219 738 504 1 16 28 164 478 566 450 402 1 16 6 350 205 6 842 140 491 935 1 16 10 326 272 10 626 763 300 491 1 16 10 326 272 10 626 763 300 491 1 16 14 876 360 16 199 483 1 323 123 1 16 15 400 547 18 072 199 2 671 653 1 16 29 320 004 30 105 652 785 648 1 16 29 502 984 30 123 121 620 137 1 16 29 502 984 30 033 300 530 316 1 16 29 502 984 30 085 308 582 324 1 16 31 977 497 32 556 470 578 973 1 16 31 977 497 32 556 470 578 973 1 16 31 977 497 32 556 470 578 973 1 16 61 723 474 61 979 447 255 973 1 16 76 753 394 77 096 916 343 522 1 16 86 279 192 86 565 924 286 732 1 16 78872764 79613942 741 178 1 16 82918034 83261468 343 434 1 17 4 246 005 4 558 547 312 542 1 17 14 041 753 15 411 904 1 370 151 1 17 14 041 753 15 411 904 1 370 151 1 17 17 349 424 17 710 177 360 753 1 17 36 732 774 36 997 679 264 905 1 18 755 919 1 841 122 1 085 203 1 18 11 920 945 12 226 187 305 242 1 18 11 920 945 12 226 187 305 242 1 18 22 626 590 22 885 652 259 062 1 18 22 626 590 22 885 652 259 062 1 18 61 928 588 62 288 983 360 395 1 18 64 084 918 64 334 903 249 985 1 19 1 566 796 2 050 820 484 024 1 19 8 232 865 8 521 268 288 403 1 19 23 412 472 23 862 137 449 665 1 20 8 047 251 8 523 332 476 081 1 20 14 800 897 15 070 049 269 152 1 20 30 958 043 40 216 806 9 258 763 1 20 41 111 842 55 338 515 14 226 673 1 21 14 401 408 14 722 833 321 425 1 21 14 524 688 14 957 973 433 285 1 21 19 201 491 20 879 211 1 677 720 1 21 32 314 674 32 580 679 266 005 1 21 18288518 19287152 998 634 1 21 19067020 20099758 1 032 739 1 22 14 836 970 15 438 616 601 646 1 22 15 333 560 17 020 300 1 686 740 1 22 21 538 519 21 981 318 442 799 1 22 25 640 628 25 910 667 270 039 1 22 26 701 485 27 253 317 551 832 1 22 45 577 231 46 087 170 509 939 1

Downloaded From: https://jamanetwork.com/ on 09/26/2021 B. List of individual duplication regions Chromosome Start Position (Hg18) End Position (Hg18) Size (bp) CNV 1 1 135 242 1 509 034 373 792 3 1 2 700 372 3 208 375 508 003 3 1 4 423 896 4 927 798 503 902 3 1 12 258 734 12 793 914 535 180 3 1 12 262 205 12 761 104 498 899 3 1 12 391 953 12 835 868 443 915 3 1 34 388 163 34 830 734 442 571 3 1 49 900 785 50 410 621 509 836 3 1 69 370 007 69 698 399 328 392 3 1 72 759 817 73 100 542 340 725 3 1 74 893 604 75 840 867 947 263 3 1 75 012 799 75 840 867 828 068 3 1 80 507 684 80 815 343 307 659 3 1 80 507 684 80 815 343 307 659 3 1 80 507 684 80 815 343 307 659 3 1 87 096 663 87 367 676 271 013 3 1 88 969 182 89 323 878 354 696 3 1 94 579 690 94 895 106 315 416 3 1 94 579 690 94 895 106 315 416 3 1 94 579 690 94 895 106 315 416 3 1 105 166 823 105 448 598 281 775 3 1 108 652 325 108 912 413 260 088 3 1 144 132 834 144 415 996 283 162 3 1 144 800 611 146 262 563 1 461 952 3 1 144 967 972 146 262 563 1 294 591 3 1 144 970 329 146 293 282 1 322 953 3 1 145 020 771 146 377 870 1 357 100 3 1 145 022 717 146 286 966 1 264 250 3 1 145 114 847 146 325 568 1 210 722 3 1 145 589 455 147 515 551 1 926 097 3 1 147 204 532 147 515 551 311 019 3 1 147 204 532 147 515 551 311 019 3 1 150 090 713 150 563 487 472 774 3 1 168 142 280 168 676 024 533 744 3 1 175 428 957 175 759 323 330 366 3 1 186 781 083 187 394 747 613 664 3 1 186 950 065 187 367 330 417 265 3 1 188 431 398 188 682 920 251 522 3 1 192 318 191 192 618 219 300 028 3 1 193 308 328 193 616 776 308 448 3 1 211 104 247 211 385 388 281 141 3 1 222 726 401 223 537 671 811 270 3 1 247 151 035 247 865 773 714 738 3 2 836 164 1 088 891 252 727 3 2 13 958 114 14 209 050 250 936 3 2 15 388 452 15 785 213 396 761 3 2 24 910 766 25 568 420 657 654 3 2 25 821 689 26 206 255 384 566 3 2 26 104 865 26 472 047 367 182 3 2 28 536 678 29 716 418 1 179 740 3 2 32 240 163 32 589 385 349 222 3 2 37 716 221 39 459 421 1 743 200 3 2 45 263 492 45 827 640 564 148 3 2 53 216 917 53 475 338 258 421 3 2 57 186 177 57 767 125 580 948 3 2 61 043 834 61 623 476 579 642 3

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 8. Education achievement in EGCUT replication cohorts separately and combined with discovery cohort

Cohort Sample MEA P-value Fraction P- OR Fraction P- OR Formatted Table size (CI95%) below value (CI95%) above value (CI95%) secondary secondary i.e. levels i.e. levels 1-3 5-7 (nb of (nb of case) case) Combined analysis of two EGCUT replication cohorts EGCUT 2051 4.36 17.7% 28.8% population (4.41; (364) (590) 4.31) 250kb 47 3.91 0.004 27.7% 0.085 1.77 10.6% 0.005 0.29 ≤ DEL (4.20; (13) (1.06; (5)** (0.09; carriers < 3.63)** 3.12) 0.75) 500kb DUP 19 3.79 0.057 42.1% 0.012 3.37 15.6% (3) 0.308 0.46 (0.09; carriers (4.34; (8)* (1.17; 1.63) ≥1Mb 3.24) 9.27) EGCUT 1043 4.50 13.3% population (4.57; (139) females 4.43) 250kb 26 3.72 0.0001 30.8% 0.019 2.89 ≤ DEL (4.04; (8)* (1.06; females < 3.40)*** 7.14) 500kb Combined analysis of EGCUT discovery and replication cohorts EGCUT 8870 4.15 23.6% 22.7% population (4.18; (2093) (2017) 4.13) 250 kb 263 3.84 4.36e- 31.9% 0.0025 1.52 14.4% 0.0012 0.57 ≤ DEL (3.97; 06 (84)** (1.15; (38)** (0.39; carriers < 3.71)*** 1.99) 0.82) 500 kb DUP 124 3.74 1.98e- 37.9% 0.0004 1.98 12.9% 0.009 0.5 (0.28; carriers ≥ 1 (3.92; 05 (47)*** (1.34; (16)** 0.86) Mb 3.56)*** 2.89) EGCUT 4539 4.22 20.3% population (4.25; (920) females 4.19) 250kb 146 3.71 3.887e- 33.6% 0.0002 1.99 ≤ DEL (3.88; 08 (49)*** (1.37; females < 3.54)*** 2.85) 500kb Education levels were coded according to the Estonian education curriculum: 1 - less than primary; 2 - primary; 3 – basic; 4 – secondary; 5 – professional higher/college; 6 – university/academic degree; 7 – scientific degree (see eMethods for more details). Statistical significance was determined by comparing the education achievements, fraction of individuals with lower and higher education of CNV carriers with those of the EGCUT population (Leitsalu, L. et al., International Journal of Epidemiology. Feb 11 2014., as well as of female CNV carriers with those of the EGCUT female population (see eMethods). Significant results are highlighted in bold; P values ≤ 0.05, ≤ 0.01 and ≤ 0.001 are pinpointed by *, ** and *** respectively. Abbreviations: MEA: mean education attainment

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 9. Mean Standard Assessment Tests (SATs) scores for English and Mathematics in ALSPAC CNV carriers Out Group1 Mean Mean P N N Standard Standard com SATs SATs va (con (CNV Deviation Deviation e (control (CNV lu trols carrie (controls) (CNV s) carriers) e ) rs) carriers) Engl 250kb≥ 0.14 0.03 0. 445 112 0.99 1.06 ish DEL<5 14 8 00kb 6 500kb≤ 0.14 -0.12 0. 445 48 0.99 1.13 DEL<1 06 8 Mb 0 DEL≥1 0.14 -0.29 0. 445 28 0.99 1.04 Mb 02 8 0* 250kb≥ 0.14 0.09 0. 445 213 0.99 1.04 DUP<5 26 8 00kb 9 500kb≤ 0.14 0.13 0. 445 134 0.99 0.87 DUP<1 46 8 Mb 1 DUP≥1 0.14 -0.16 0. 445 47 0.99 0.95 Mb 02 8 0*

Mat 250kb≥ 0.15 -0.05 0. 457 115 0.98 1.01 hem DEL<5 01 9 atics 00kb 9* 500kb≤ 0.15 -0.09 0. 457 50 0.98 1.00 DEL<1 05 9 Mb 3 DEL≥1 0.15 -0.42 0. 457 32 0.98 1.09 Mb 00 9 3** 250kb≥ 0.15 0.09 0. 457 215 0.98 0.96 DUP<5 20 9 00kb 3 500kb≤ 0.15 0.13 0. 457 140 0.98 0.89 DUP<1 38 9 Mb 6 DUP≥1 0.15 -0.11 0. 457 48 0.98 1.03 Mb 04 9 9* Comparison of means of educational achievement for English and Mathematics, according to CNV size (carrier frequency ≤ 0.05%). English and Mathematics SATs scores were inverse rank transformed and standardized. P values are for a Welch two-sided t-test. Statistical significance was determined as P value ≤ 0.05. Significant results are highlighted in bold; P values ≤ 0.05, ≤ 0.01 and ≤ 0.001 are pinpointed by *, ** and *** respectively. Abbreviations: DEL: deletion; DUP: duplication

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 10: Education attainment in Italian HYPERGENES cohort Cohort Sample size MEA (CI95%) P-value P-value (Wilcoxon test) (Welch test) Controls 354 2.66 (2.54; 2.77)

250kb ≤ DEL carriers < 500kb 29 2.69 (2.23; 3.15) 0.437 0.556

500kb ≤ DEL carriers < 1Mb 10 2.40 (1.88; 2.92) 0.390 0.186

DEL carriers ≥1Mb 4 2.50 (0.46; 4.54) 0.435 0.445

250kb ≤ DUP carriers < 500kb 37 2.81 (2.34; 3.28) 0.621 0.735

500kb ≤ DUP carriers < 1Mb 25 2.60 (2.13; 3.07) 0.453 0.412

DUP carriers ≥1Mb 4 2.00 (1.20; 2.80) 0.113 0.103

Due to small sample size the rare CNV threshold in HYPERGENES cohort was set to the carrier frequency of ≥0.25% (i.e. 5-fold higher than in other analyzed cohorts). Statistical significance was determined as P value ≤ 0.05. Abbreviations: DEL: deletion; DUP: duplication; MEA: mean education attainment

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 11: Education attainment in European American MCTFR cohort Sample Cohort Mean IQ Δ IQ Standard Error P-value size Formatted Table MCTFR 2390 104.52 250 kb 29 103.3103 -0.75496 2.646237 0.78 ≤ DEL carriers < 500 kb 500 kb 7 100.4286 -4.22753 5.358951 0.43 ≤ DEL carriers < 1Mb DEL carriers ≥1Mb 3 91.33 -13.8162 8.173657 0.09 DEL carriers ≥250kb 37 101.70 -2.4980 2.3461 0.29 DEL carriers ≥500kb 10 97.70 -7.1177 4.4834 0.11 250 kb 62 106.6156 1.94117 1.821325 0.29 ≤ DUP carriers < 500 kb 500 kb 40 98.7125 -5.56119 2.254786 0.01** ≤ DUP carriers < 1Mb DUP carriers ≥1Mb 11 98.09 -6.0297 4.2763 0.16 DUP carriers ≥250kb 108 103.3025 -1.27254 1.39359 0.36 DUP carriers ≥500kb 50 98.70 -5.5851 2.0205 0.005** MCTFR females 1296 103.91 DEL females ≥500kb 5 89.96 -13.7266 6.2408 0.03* DUP females ≥500kb 28 99.59 -4.3152 2.6649 0.11 MCTFR males 1094 105.24 DEL males ≥500kb 5 105.12 -0.12248 6.4322 0.98 DUP males ≥500kb 22 105.12 -7.0687 3.0780 0.02* Statistical significance was determined using linear regression adjusting for age and sex (when applicable). Significant results are highlighted in bold; P values ≤ 0.05, ≤ 0.01 and ≤ 0.001 are pinpointed by *, ** and *** respectively.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 12. MetaCore Enrichment by GO Processes analysis report # GO process Total p-value FDR In Network Objects Data 1 startle 41 6,215E- 2,209E- 12 Neurexin beta, PTEN, Protocadherin 15, Neurexin response 10 06 alpha, Neurexin 1-alpha, Ionotropic glutamate receptor, NR2A, Dsh, NR2, Neurexin 1-beta, DVL-1, Parkin 2 behavior 734 1,261E- 2,209E- 51 AGTR1, VWA1, Neurexin beta, PLA2, HOXD9, 09 06 PTEN, MSS51, HOXD10, Protocadherin 15, GluR5, CHL1, mGluR7, Neurexin alpha, POMC, PDE, SEZ6L2, mGluR5, Neurexin 1-alpha, Galpha(q)- specific metabotropic glutamate GPCRs, HtrA2, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, NR2A, FGF14, Dsh, NTAN1, NR2, ZNF378, PACAP, Neurexin 1- beta, NPC1, G-protein alpha-i family, H-Ras, Adenylate cyclase, C1orf25, NCOA1 (SRC1), DVL- 1, Substance P receptor, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, SCAMP4, EPS8, Tissue kallikreins, Adenylate cyclase type VIII, PLC-beta1, COMT, Parkin, Calcineurin A (beta), Kainate receptor, Nephrocystin, PLC-beta 3 neuron 1080 2,240E- 2,209E- 65 Contactin 4, MYH11, Smooth muscle myosin, development 09 06 CNTN6, Neurexin beta, PLA2, Chapsyn-110, G- protein alpha-t, HOXD9, PTEN, Transducin, rod- specific, WNT3A, HOXD10, Protocadherin 15, CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, PDE, B3GN1, Neurotrimin, Neurexin 1-alpha, Spinophilin, HtrA2, CBFB/MYH11 fusion protein, MyHC, Carbohydrate sulfotransferases, Galpha(i)- specific metabotropic glutamate GPCRs, Agrin, Glypican-1, COL4A2, Dsh, WNT, RP1L1, PACAP, MYR8, JNK(MAPK8-10), SOX1, MICAL-L2, Neurexin 1-beta, Semaphorin 4F, G-protein alpha-i family, Sec24, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL-1, Calcineurin A (catalytic), Galpha(q)- specific peptide GPCRs, CYFIP1, GPR98, PLA2G10, Tissue kallikreins, Semaphorin 6D, Large LDL, Endophilin A1, CAPZ beta, Semaphorin 3F, Parkin, Calcineurin A (beta), RTN4R, Nephrocystin, Collagen IV, Plexin A4 4 metabolic 11372 2,347E- 2,209E- 380 C2orf65, RPS28, p160, PINX1, PTSS2, OATP8, process 09 06 AGTR1, TRMU, PDE3A, HSST2, XRCC3, NOX4, YES, APOB, PRPF4, Syntaxin 17, HEPHL1, IMPA2, BUB1, RNPEPL1, C3orf21, HES4, FMO3, MYH11, BTEB4, FHL2, Cereblon, ERp44, MPV17L, FMO6P, Smooth muscle myosin, INTS1, DPEP3, NDUFA7, POLE3-POLE4 complex, HDLBP, Ribonuclease H1, HYAL2, Glycogenin-1, FMO4, PLA2, Chapsyn-110, SPEF2, CDC42BPB, G-protein alpha-t, InPP5A, Kinesin light chain, E2A, LBX2, TXNRD2, MSRA, GALNT13, HOXD9, CDC26, PTEN, BLK, CPA4, ADAT1, SC4MOL, Helios, Transducin, rod-specific, GATE-16, RNASE9, HOXD10, TTC5 (Strap), FLJ20297, FKBP15, FUS2, DCTD, IRS-2, D15Wsu75e, RING2, ZNF716, VRK1, Dusp28, DNAH14, PDIP1, PLK5, ALDP, ARG1, OSGEP, HDHD3, KLC1, Calpastatin, SIAT8D, PTB2, TLL1, Limkain b1, TAO2, CCDC95, POMC, UQCR11, 3- OST-3B, PDE, FAM108A1, E2A/HLF fusion protein, POU3F3 (BRN1), UGT3A2, MRPL19, HXK2, LP8165, ZNF664, MRPS9, RABL2A, PTPN18, DDX43, ABCC1, NDUFA10, Carboxypeptidase H, CCNL2, DUSP19, RNF4, ENPP1, mGluR5, IMP4, Glis2, UBE3A (E6-AP), B3GN1, HOXD12, Dexras1, SUMF1, MRPL20, RRN3, LDL, DPY19L2, ZNF370, NS1-BP, DES1, ATHL1, RBM6, HOX11L1, CDIPT, Tex1, TFCP2L2, UGT3A1, Galpha(q)-specific metabotropic glutamate GPCRs, Spinophilin, Small LDL, ASPHD1, HtrA2, GATA-4, FMO2, KCRB, CBFB/MYH11 fusion protein, LMNBR, PCTK3, MyHC, SIA7C, AMN, B4GALNT4, Tcf(Lef), Casein kinase I, RAI, DDX11, Carbohydrate sulfotransferases, DOM3Z, Ionotropic glutamate receptor, GCS1, ZNF267, NEIL2, Agrin, MTMR9,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 Dynein, axonemal, heavy chains, TTLL10, C13orf39, OOEP, FLJ10769, PARP-2, ATAD3B, MVP, CD320, Glypican-1, COL4A2, TCF7L1 (TCF3), DNAH10, HOXD11, Ggt6, NR2A, HOXD4, RIOK3, ADSS, Casein kinase I gamma 2, FDFT1, Actifilin, SPPL2b, PAPA1, Dsh, WNT, ZNF91, NTAN1, ABHD13, TMEM166, SULT1A3, ELKS, NR2, ZNF378, SCOP, KIF1A, MEX3D, PACAP, MC-CPA, MYR8, UBC7, PDE3, A20, JNK(MAPK8- 10), DGCR8, SOX1, PEMT, HOXD8, PAF49, MBLAC2, CPB1, HOXD1, APEX, PUSL1, NPC1, TINAGL1, G-protein alpha-i family, MPP2, Kid, eIF5, Sec24, PTPN20B, NAR4, SP-D, SAC, MARK3, ATF7IP2, MAZ, ZDHHC20, Foxd4L1, G-protein alpha-i2, NOC2L, Metaxin 2, COL4A1, NRIP, HEM2, Sec24C, SgK223, TPP2, Kif2a, H-Ras, Adenylate cyclase, C1orf25, RBM5, NCOA1 (SRC1), RNASE12, GIYD1 (SLX1), ONECUT3, CARS2, DVL-1, LOXL3, 2410004A20Rik, Calcineurin A (catalytic), ADAT3, GCF, SPNS2, Galpha(q)-specific peptide GPCRs, NUP35, HOXD13, PC1, RNASE11, Tubulin alpha, DNMT3A, SOX7, Creatine kinase, STK39, HEI10, USP54, FUT11, COX10, RIPK5, CENPO, TMEM55B, GALNTL2, PLAU (UPA), Hyaluronidase, DQX1, JNK3(MAPK10), PNPH, MPV17, DUB3, CHST5, PLA2G10, AUP1, ADSSL1, SNRPN, ATAD3C, REXO1, Calpain 10, HOXD3, C16orf53, Tissue kallikreins, POLE4, Cathepsin B, TEP1, Kallikrein 2, Lysmd3, PCGF1, MBD3, OLIG3, POLR3G, TYRO, Adenylate cyclase type VIII, MUC1, CHKB, PLC- beta1, TRNT1, DNA ligase IV, CaMK II gamma, AKIP, HYAL3, KLHL2, Large LDL, MED9, C6orf150, MARCH1, PPP1R3B, PRSS55, Enteropeptidase, NUAK2, Klotho, A2BP1, AGXT, CTGF, TRIML1, C2orf79, ATP8B3, MRCK, HTF9C, Rnase10, DEAF, Adenylate cyclase type III, NADC, MPN2, COMT, NVL, Parkin, UBE2J2, Calcineurin A (beta), Pc2, ZNF678, Tubulin alpha 3E, ZNF730, INTS11, SETMAR, ZNF724P, TRM61, BAG5, BRP44, Poly(A) polymerase, mTERFD2, POU class III, TXNDC13, B3GT6, GPAT2, Tankyrase 1, TRAF3, OST48, ENPP3, PASK, UBC6, LASS4, 3'HEXO, Galpha(t)-specific GPCRs, ZNF717, HYAL1, FAM152A, DRIP130, Uncx, CHCHD3, ACOXL, Collagen IV, PLC-beta, ISG15, IGFBP7/8, UBE2G1, ANAPC1, CHST6 5 neuron 1311 2,590E- 2,209E- 74 Contactin 4, MYH11, Smooth muscle myosin, differentiation 09 06 CNTN6, Neurexin beta, PLA2, Chapsyn-110, G- protein alpha-t, HOXD9, PTEN, Transducin, rod- specific, WNT3A, HOXD10, Protocadherin 15, CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, PDE, B3GN1, Neurotrimin, WNT9A, Neurexin 1- alpha, Spinophilin, HtrA2, Nkx6-2, CBFB/MYH11 fusion protein, MyHC, Tcf(Lef), Carbohydrate sulfotransferases, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, Agrin, Chordin-like 1, Glypican-1, COL4A2, Dsh, WNT, RP1L1, PACAP, MYR8, JNK(MAPK8-10), SOX1, MICAL-L2, Neurexin 1-beta, HOXD1, Semaphorin 4F, G-protein alpha-i family, Sec24, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL- 1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, CYFIP1, GPR98, PLA2G10, Tissue kallikreins, OLIG3, Semaphorin 6D, Large LDL, Endophilin A1, CAPZ beta, Semaphorin 3F, Parkin, Calcineurin A (beta), RTN4R, POU class III, Nephrocystin, Uncx, Collagen IV, Plexin A4 6 glutamate 56 2,801E- 2,209E- 13 GluR5, mGluR7, mGluR5, Galpha(q)-specific receptor 09 06 metabotropic glutamate GPCRs, Ionotropic signaling glutamate receptor, Galpha(i)-specific metabotropic pathway glutamate GPCRs, NR2A, NR2, G-protein alpha-i family, G-protein alpha-i2, PLC-beta1, Kainate receptor, PLC-beta 7 nervous 2609 2,897E- 2,209E- 121 Contactin 4, APOB, LRRTM4, HES4, MYH11,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 system 09 06 Complexin, Smooth muscle myosin, CNTN6, development Neurexin beta, PLA2, Chapsyn-110, SPEF2, G- protein alpha-t, E2A, HOXD9, BETA-PIX, PTEN, Transducin, rod-specific, WNT3A, HOXD10, Protocadherin 15, IRS-2, LRCH4, GluR5, CHL1, PLK5, Olfactory receptor, Calpastatin, SIAT8D, Neurexin alpha, PDE, E2A/HLF fusion protein, POU3F3 (BRN1), SEZ6L2, mGluR5, Glis2, UBE3A (E6-AP), B3GN1, Neurotrimin, LDL, WNT9A, Neurexin 1-alpha, HOX11L1, Galpha(q)-specific metabotropic glutamate GPCRs, ODZ3, Spinophilin, Small LDL, HtrA2, Nkx6-2, KCRB, CBFB/MYH11 fusion protein, MyHC, Tcf(Lef), Complexin 2, Carbohydrate sulfotransferases, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, Agrin, Cab45, Chordin-like 1, Glypican-1, COL4A2, TCF7L1 (TCF3), NR2A, FGF14, Actifilin, Dsh, WNT, RP1L1, NR2, PACAP, MYR8, JNK(MAPK8-10), SOX1, MICAL-L2, Neurexin 1-beta, Bim, HOXD1, Semaphorin 4F, G- protein alpha-i family, Sec24, Foxd4L1, COL4A1, Kif2a, H-Ras, Adenylate cyclase, NCOA1 (SRC1), DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, NudE, PC1, CYFIP1, Creatine kinase, GPR98, PLA2G10, HOXD3, Tissue kallikreins, OLIG3, PLC-beta1, PMP22, DNA ligase IV, Semaphorin 3D, CaMK II gamma, ERC2/CAST, Semaphorin 6D, Large LDL, Endophilin A1, DEAF, CAPZ beta, Semaphorin 3F, Parkin, Calcineurin A (beta), RTN4R, POU class III, Kainate receptor, Nephrocystin, Uncx, Collagen IV, PLC-beta, Plexin A4 8 receptor 50 7,625E- 5,087E- 12 LRRTM4, Neurexin beta, Chapsyn-110, Neurexin clustering 09 06 alpha, Neurexin 1-alpha, Ionotropic glutamate receptor, Agrin, Dsh, NR2, Neurexin 1-beta, DVL-1, Kainate receptor 9 neuromuscular 139 8,805E- 5,222E- 19 Neurexin beta, PTEN, HOXD10, Protocadherin 15, process 09 06 Neurexin alpha, Neurexin 1-alpha, Nkx6-2, MyHC, Ionotropic glutamate receptor, NR2A, FGF14, Dsh, NR2, Neurexin 1-beta, Adenylate cyclase, DVL-1, PRRT2, A2BP1, Parkin 10 single- 622 1,070E- 5,713E- 44 VWA1, Neurexin beta, PLA2, HOXD9, PTEN, organism 08 06 HOXD10, Protocadherin 15, GluR5, CHL1, mGluR7, behavior Neurexin alpha, PDE, SEZ6L2, mGluR5, Neurexin 1-alpha, Galpha(q)-specific metabotropic glutamate GPCRs, HtrA2, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, NR2A, FGF14, NTAN1, NR2, ZNF378, PACAP, Neurexin 1-beta, NPC1, G-protein alpha-i family, H- Ras, Adenylate cyclase, C1orf25, Substance P receptor, Calcineurin A (catalytic), Galpha(q)- specific peptide GPCRs, EPS8, Tissue kallikreins, Adenylate cyclase type VIII, PLC-beta1, COMT, Parkin, Calcineurin A (beta), Kainate receptor, Nephrocystin, PLC-beta 11 neurogenesis 1839 2,148E- 1,042E- 91 Contactin 4, MYH11, Smooth muscle myosin, 08 05 CNTN6, Neurexin beta, PLA2, Chapsyn-110, G- protein alpha-t, E2A, HOXD9, BETA-PIX, PTEN, Transducin, rod-specific, WNT3A, HOXD10, Protocadherin 15, CHL1, PLK5, Olfactory receptor, SIAT8D, Neurexin alpha, PDE, E2A/HLF fusion protein, mGluR5, B3GN1, Neurotrimin, WNT9A, Neurexin 1-alpha, HOX11L1, Galpha(q)-specific metabotropic glutamate GPCRs, ODZ3, Spinophilin, HtrA2, Nkx6-2, CBFB/MYH11 fusion protein, MyHC, Tcf(Lef), Carbohydrate sulfotransferases, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, Agrin, Chordin-like 1, Glypican- 1, COL4A2, TCF7L1 (TCF3), NR2A, Dsh, WNT, RP1L1, NR2, PACAP, MYR8, JNK(MAPK8-10), SOX1, MICAL-L2, Neurexin 1-beta, HOXD1, Semaphorin 4F, G-protein alpha-i family, Sec24, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, NCOA1 (SRC1), DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, NudE, PC1,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 CYFIP1, GPR98, PLA2G10, HOXD3, Tissue kallikreins, OLIG3, PMP22, DNA ligase IV, Semaphorin 6D, Large LDL, Endophilin A1, CAPZ beta, Semaphorin 3F, Parkin, Calcineurin A (beta), RTN4R, POU class III, Nephrocystin, Uncx, Collagen IV, Plexin A4 12 generation of 1744 3,221E- 1,422E- 87 Contactin 4, MYH11, Smooth muscle myosin, neurons 08 05 CNTN6, Neurexin beta, PLA2, Chapsyn-110, G- protein alpha-t, E2A, HOXD9, PTEN, Transducin, rod-specific, WNT3A, HOXD10, Protocadherin 15, CHL1, PLK5, Olfactory receptor, SIAT8D, Neurexin alpha, PDE, E2A/HLF fusion protein, mGluR5, B3GN1, Neurotrimin, WNT9A, Neurexin 1-alpha, HOX11L1, Galpha(q)-specific metabotropic glutamate GPCRs, ODZ3, Spinophilin, HtrA2, Nkx6- 2, CBFB/MYH11 fusion protein, MyHC, Tcf(Lef), Carbohydrate sulfotransferases, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, Agrin, Chordin-like 1, Glypican- 1, COL4A2, TCF7L1 (TCF3), Dsh, WNT, RP1L1, PACAP, MYR8, JNK(MAPK8-10), SOX1, MICAL-L2, Neurexin 1-beta, HOXD1, Semaphorin 4F, G-protein alpha-i family, Sec24, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, NCOA1 (SRC1), DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, NudE, CYFIP1, GPR98, PLA2G10, HOXD3, Tissue kallikreins, OLIG3, PMP22, DNA ligase IV, Semaphorin 6D, Large LDL, Endophilin A1, CAPZ beta, Semaphorin 3F, Parkin, Calcineurin A (beta), RTN4R, POU class III, Nephrocystin, Uncx, Collagen IV, Plexin A4 13 adult behavior 217 3,465E- 1,422E- 23 Neurexin beta, HOXD9, HOXD10, Protocadherin 15, 08 05 GluR5, CHL1, mGluR7, Neurexin alpha, SEZ6L2, Neurexin 1-alpha, HtrA2, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, FGF14, NTAN1, NR2, Neurexin 1-beta, NPC1, C1orf25, Galpha(q)-specific peptide GPCRs, EPS8, Parkin, Kainate receptor 14 G-protein 21 4,549E- 1,734E- 8 mGluR7, mGluR5, Galpha(q)-specific metabotropic coupled 08 05 glutamate GPCRs, Ionotropic glutamate receptor, glutamate Galpha(i)-specific metabotropic glutamate GPCRs, receptor G-protein alpha-i family, G-protein alpha-i2, Kainate signaling receptor pathway 15 locomotory 257 4,898E- 1,743E- 25 HOXD9, PTEN, HOXD10, Protocadherin 15, CHL1, behavior 08 05 PDE, SEZ6L2, mGluR5, Galpha(q)-specific metabotropic glutamate GPCRs, HtrA2, Galpha(i)- specific metabotropic glutamate GPCRs, NR2A, FGF14, NTAN1, NR2, ZNF378, NPC1, G-protein alpha-i family, Adenylate cyclase, C1orf25, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, EPS8, Parkin, Calcineurin A (beta) 16 intraspecies 59 5,615E- 1,763E- 12 Neurexin beta, PTEN, MSS51, Neurexin alpha, interaction 08 05 Neurexin 1-alpha, Dsh, Neurexin 1-beta, H-Ras, between DVL-1, Calcineurin A (catalytic), Galpha(q)-specific organisms peptide GPCRs, Calcineurin A (beta) 17 social behavior 59 5,615E- 1,763E- 12 Neurexin beta, PTEN, MSS51, Neurexin alpha, 08 05 Neurexin 1-alpha, Dsh, Neurexin 1-beta, H-Ras, DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, Calcineurin A (beta) 18 learning 174 7,085E- 1,997E- 20 Neurexin beta, mGluR7, Neurexin alpha, PDE, 08 05 mGluR5, Neurexin 1-alpha, Galpha(q)-specific metabotropic glutamate GPCRs, Galpha(i)-specific metabotropic glutamate GPCRs, NR2A, NR2, Neurexin 1-beta, H-Ras, Substance P receptor, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, PLC-beta1, COMT, Parkin, Calcineurin A (beta), PLC-beta 19 memory 142 7,108E- 1,997E- 18 PLA2, PTEN, mGluR7, PDE, Ionotropic glutamate 08 05 receptor, Galpha(i)-specific metabotropic glutamate GPCRs, NR2A, NTAN1, NR2, Adenylate cyclase, Substance P receptor, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, Tissue kallikreins, Adenylate cyclase type VIII, PLC-beta1, Calcineurin A (beta), PLC-beta

Downloaded From: https://jamanetwork.com/ on 09/26/2021 20 cognition 323 9,170E- 2,447E- 28 Neurexin beta, PLA2, PTEN, CHL1, mGluR7, 08 05 Neurexin alpha, PDE, mGluR5, Neurexin 1-alpha, Galpha(q)-specific metabotropic glutamate GPCRs, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, NR2A, NTAN1, NR2, Neurexin 1-beta, H-Ras, Adenylate cyclase, Substance P receptor, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, Tissue kallikreins, Adenylate cyclase type VIII, PLC-beta1, COMT, Parkin, Calcineurin A (beta), PLC-beta 21 learning or 306 1,087E- 2,762E- 27 Neurexin beta, PLA2, PTEN, mGluR7, Neurexin memory 07 05 alpha, PDE, mGluR5, Neurexin 1-alpha, Galpha(q)- specific metabotropic glutamate GPCRs, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, NR2A, NTAN1, NR2, Neurexin 1-beta, H-Ras, Adenylate cyclase, Substance P receptor, Calcineurin A (catalytic), Galpha(q)- specific peptide GPCRs, Tissue kallikreins, Adenylate cyclase type VIII, PLC-beta1, COMT, Parkin, Calcineurin A (beta), PLC-beta 22 positive 32 1,323E- 3,210E- 9 AGTR1, APOB, PLA2, LDL, Small LDL, regulation of 07 05 JNK(MAPK8-10), Galpha(q)-specific peptide macrophage GPCRs, PLA2G10, Large LDL derived foam cell differentiation 23 cellular 9779 1,396E- 3,239E- 329 RPS28, C2orf65, PINX1, p160, PTSS2, OATP8, metabolic 07 05 AGTR1, TRMU, PDE3A, HSST2, XRCC3, NOX4, process YES, APOB, PRPF4, Syntaxin 17, IMPA2, BUB1, RNPEPL1, HES4, FMO3, BTEB4, FHL2, Cereblon, ERp44, MPV17L, INTS1, Smooth muscle myosin, NDUFA7, POLE3-POLE4 complex, Ribonuclease H1, Glycogenin-1, FMO4, PLA2, Chapsyn-110, SPEF2, CDC42BPB, InPP5A, G-protein alpha-t, E2A, LBX2, MSRA, GALNT13, HOXD9, CDC26, PTEN, BLK, CPA4, ADAT1, SC4MOL, Helios, Transducin, rod-specific, GATE-16, RNASE9, HOXD10, TTC5 (Strap), FLJ20297, FKBP15, DCTD, RING2, ZNF716, VRK1, Dusp28, PDIP1, ALDP, PLK5, ARG1, OSGEP, PTB2, SIAT8D, Limkain b1, TAO2, CCDC95, POMC, UQCR11, 3- OST-3B, PDE, E2A/HLF fusion protein, POU3F3 (BRN1), MRPL19, HXK2, LP8165, ZNF664, MRPS9, RABL2A, PTPN18, DDX43, ABCC1, NDUFA10, Carboxypeptidase H, CCNL2, DUSP19, RNF4, ENPP1, IMP4, mGluR5, Glis2, UBE3A (E6- AP), Dexras1, B3GN1, HOXD12, SUMF1, MRPL20, RRN3, LDL, ZNF370, NS1-BP, DES1, RBM6, HOX11L1, CDIPT, Tex1, TFCP2L2, Galpha(q)- specific metabotropic glutamate GPCRs, Spinophilin, Small LDL, ASPHD1, HtrA2, GATA-4, FMO2, KCRB, CBFB/MYH11 fusion protein, PCTK3, MyHC, SIA7C, AMN, Tcf(Lef), Casein kinase I, RAI, DDX11, Carbohydrate sulfotransferases, DOM3Z, Ionotropic glutamate receptor, GCS1, ZNF267, NEIL2, Agrin, MTMR9, Dynein, axonemal, heavy chains, TTLL10, C13orf39, OOEP, PARP-2, CD320, Glypican-1, TCF7L1 (TCF3), COL4A2, DNAH10, HOXD11, Ggt6, NR2A, HOXD4, ADSS, RIOK3, Casein kinase I gamma 2, FDFT1, Actifilin, Dsh, PAPA1, WNT, ZNF91, TMEM166, SULT1A3, NR2, ELKS, ZNF378, SCOP, MEX3D, PACAP, MC-CPA, UBC7, PDE3, A20, JNK(MAPK8-10), DGCR8, SOX1, PEMT, HOXD8, PAF49, HOXD1, APEX, PUSL1, NPC1, Kid, G-protein alpha-i family, MPP2, eIF5, Sec24, PTPN20B, NAR4, SP-D, SAC, MARK3, MAZ, ATF7IP2, Foxd4L1, G-protein alpha-i2, NOC2L, Metaxin 2, HEM2, NRIP, Sec24C, SgK223, TPP2, H-Ras, Adenylate cyclase, C1orf25, RBM5, RNASE12, NCOA1 (SRC1), GIYD1 (SLX1), ONECUT3, CARS2, DVL-1, 2410004A20Rik, Calcineurin A (catalytic), ADAT3, GCF, SPNS2, Galpha(q)-specific peptide GPCRs, HOXD13, PC1, RNASE11, Tubulin alpha, DNMT3A, SOX7,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 Creatine kinase, STK39, HEI10, USP54, FUT11, COX10, RIPK5, CENPO, GALNTL2, PLAU (UPA), DQX1, JNK3(MAPK10), PNPH, MPV17, DUB3, CHST5, PLA2G10, ADSSL1, SNRPN, REXO1, Calpain 10, HOXD3, C16orf53, Tissue kallikreins, POLE4, Cathepsin B, TEP1, Kallikrein 2, Lysmd3, PCGF1, MBD3, OLIG3, POLR3G, TYRO, Adenylate cyclase type VIII, MUC1, CHKB, PLC-beta1, TRNT1, DNA ligase IV, CaMK II gamma, AKIP, KLHL2, Large LDL, MED9, C6orf150, MARCH1, PPP1R3B, NUAK2, Klotho, A2BP1, AGXT, CTGF, TRIML1, C2orf79, ATP8B3, MRCK, HTF9C, Rnase10, DEAF, Adenylate cyclase type III, NADC, COMT, Parkin, UBE2J2, Calcineurin A (beta), Pc2, ZNF678, ZNF730, Tubulin alpha 3E, INTS11, ZNF724P, SETMAR, TRM61, BAG5, BRP44, Poly(A) polymerase, mTERFD2, POU class III, B3GT6, GPAT2, Tankyrase 1, TRAF3, OST48, ENPP3, PASK, UBC6, LASS4, 3'HEXO, Galpha(t)- specific GPCRs, ZNF717, HYAL1, DRIP130, Uncx, CHCHD3, ACOXL, Collagen IV, PLC-beta, ISG15, IGFBP7/8, UBE2G1, ANAPC1, CHST6 24 regulation of 65 1,739E- 3,867E- 12 Neurexin beta, PLA2, GluR5, Neurexin alpha, synaptic 07 05 Neurexin 1-alpha, Galpha(q)-specific metabotropic transmission, glutamate GPCRs, Ionotropic glutamate receptor, glutamatergic Galpha(i)-specific metabotropic glutamate GPCRs, PACAP, Neurexin 1-beta, Galpha(q)-specific peptide GPCRs, Kainate receptor 25 prepulse 25 2,194E- 4,684E- 8 Neurexin beta, PTEN, Neurexin alpha, Neurexin 1- inhibition 07 05 alpha, Ionotropic glutamate receptor, Dsh, Neurexin 1-beta, DVL-1 26 multi-organism 107 2,311E- 4,744E- 15 Neurexin beta, PTEN, MSS51, Neurexin alpha, behavior 07 05 Neurexin 1-alpha, Dsh, NR2, Neurexin 1-beta, H- Ras, NCOA1 (SRC1), DVL-1, Substance P receptor, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, Calcineurin A (beta) 27 regulation of 81 2,972E- 5,874E- 13 PLA2, IRS-2, GluR5, ARG1, mGluR7, Galpha(q)- organic acid 07 05 specific metabotropic glutamate GPCRs, Ionotropic transport glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, NR2, JNK(MAPK8-10), Galpha(q)-specific peptide GPCRs, PLA2G10, Kainate receptor 28 locomotion 1402 4,046E- 7,711E- 71 Contactin 4, AGTR1, YES, APOB, MYH11, Smooth 07 05 muscle myosin, CD43, CNTN6, HYAL2, Neurexin beta, PLA2, CDC42BPB, PTEN, BETA-PIX, WNT3A, CHL1, PDIP1, Olfactory receptor, CXADR, SIAT8D, Neurexin alpha, TAO2, PDE, POU3F3 (BRN1), RABL2A, ABCC1, B3GN1, LDL, Neurexin 1-alpha, Spinophilin, Small LDL, CBFB/MYH11 fusion protein, MyHC, Tcf(Lef), Carbohydrate sulfotransferases, Agrin, Dynein, axonemal, heavy chains, Glypican-1, COL4A2, NR2A, Dsh, WNT, NR2, SOX1, Neurexin 1-beta, Semaphorin 4F, SP- D, Foxd4L1, COL4A1, H-Ras, DVL-1, Calcineurin A (catalytic), SPNS2, NudE, Galpha(q)-specific peptide GPCRs, PLAU (UPA), EPS8, PLA2G10, OLIG3, Semaphorin 6D, Large LDL, Endophilin A1, CTGF, MRCK, Semaphorin 3F, Calcineurin A (beta), POU class III, Galpha(t)-specific GPCRs, Collagen IV, IGFBP7/8, Plexin A4 29 fertilization 214 4,992E- 8,949E- 21 APOB, SPEF2, HOXD9, HOXD10, Olfactory 07 05 receptor, Calpastatin, TUBGCP3, RABL2A, UBE3A (E6-AP), LDL, Small LDL, OOEP, HOXD11, C13orf28, Hyaluronidase, Tissue kallikreins, PLC- beta1, Large LDL, ATP8B3, Rnase10, PLC-beta 30 cell projection 1195 5,030E- 8,949E- 63 Contactin 4, FLJ22167, MYH11, Smooth muscle organization 07 05 myosin, CNTN6, ARHGEF4, Neurexin beta, PLA2, SPEF2, PTEN, BETA-PIX, WNT3A, Protocadherin 15, CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, RABL2A, B3GN1, Neurexin 1-alpha, C16orf63, Spinophilin, CBFB/MYH11 fusion protein, MyHC, Carbohydrate sulfotransferases, Galpha(i)- specific metabotropic glutamate GPCRs, Agrin, Dynein, axonemal, heavy chains, Glypican-1, COL4A2, Dsh, WNT, RP1L1, SPAG16, PACAP,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 MYR8, JNK(MAPK8-10), MICAL-L2, Neurexin 1- beta, Semaphorin 4F, G-protein alpha-i family, Sec24, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL-1, Calcineurin A (catalytic), Galpha(q)- specific peptide GPCRs, CYFIP1, GPR98, PLA2G10, Tissue kallikreins, Semaphorin 6D, Large LDL, Endophilin A1, CAPZ beta, Semaphorin 3F, Calcineurin A (beta), RTN4R, Nephrocystin, Collagen IV, Plexin A4 31 gamma- 4 5,615E- 9,666E- 4 Neurexin beta, Neurexin alpha, Neurexin 1-alpha, aminobutyric 07 05 Neurexin 1-beta acid receptor clustering 32 organic 10290 7,901E- 1,283E- 339 RPS28, C2orf65, PINX1, p160, PTSS2, OATP8, substance 07 04 AGTR1, TRMU, PDE3A, HSST2, XRCC3, NOX4, metabolic YES, APOB, PRPF4, IMPA2, BUB1, RNPEPL1, process HES4, BTEB4, FHL2, Cereblon, ERp44, INTS1, Smooth muscle myosin, DPEP3, POLE3-POLE4 complex, HDLBP, Ribonuclease H1, HYAL2, Glycogenin-1, PLA2, Chapsyn-110, SPEF2, CDC42BPB, InPP5A, G-protein alpha-t, E2A, LBX2, MSRA, GALNT13, HOXD9, CDC26, PTEN, BLK, CPA4, ADAT1, SC4MOL, Helios, Transducin, rod- specific, RNASE9, HOXD10, TTC5 (Strap), FLJ20297, FKBP15, DCTD, IRS-2, D15Wsu75e, RING2, ZNF716, VRK1, Dusp28, PDIP1, ALDP, PLK5, ARG1, OSGEP, Calpastatin, PTB2, SIAT8D, Limkain b1, TLL1, TAO2, CCDC95, POMC, 3-OST- 3B, PDE, E2A/HLF fusion protein, POU3F3 (BRN1), MRPL19, HXK2, LP8165, ZNF664, MRPS9, RABL2A, PTPN18, DDX43, ABCC1, NDUFA10, Carboxypeptidase H, CCNL2, DUSP19, RNF4, ENPP1, IMP4, mGluR5, Glis2, UBE3A (E6-AP), Dexras1, B3GN1, HOXD12, SUMF1, MRPL20, RRN3, LDL, ZNF370, NS1-BP, DES1, ATHL1, RBM6, HOX11L1, CDIPT, Tex1, TFCP2L2, Galpha(q)-specific metabotropic glutamate GPCRs, Spinophilin, Small LDL, ASPHD1, HtrA2, GATA-4, FMO2, KCRB, CBFB/MYH11 fusion protein, LMNBR, PCTK3, MyHC, SIA7C, AMN, Tcf(Lef), Casein kinase I, RAI, DDX11, Carbohydrate sulfotransferases, DOM3Z, Ionotropic glutamate receptor, GCS1, ZNF267, NEIL2, Agrin, Dynein, axonemal, heavy chains, TTLL10, C13orf39, OOEP, PARP-2, MVP, CD320, Glypican-1, TCF7L1 (TCF3), COL4A2, DNAH10, HOXD11, Ggt6, NR2A, HOXD4, ADSS, RIOK3, Casein kinase I gamma 2, FDFT1, Actifilin, SPPL2b, Dsh, PAPA1, WNT, ZNF91, SULT1A3, NR2, ELKS, ZNF378, SCOP, MEX3D, PACAP, MC-CPA, UBC7, PDE3, A20, JNK(MAPK8- 10), DGCR8, SOX1, PEMT, HOXD8, CPB1, PAF49, HOXD1, APEX, PUSL1, NPC1, Kid, G-protein alpha-i family, MPP2, TINAGL1, eIF5, Sec24, PTPN20B, NAR4, SAC, MARK3, MAZ, ATF7IP2, Foxd4L1, G-protein alpha-i2, NOC2L, COL4A1, Metaxin 2, HEM2, NRIP, Sec24C, SgK223, TPP2, H-Ras, Adenylate cyclase, C1orf25, RBM5, RNASE12, NCOA1 (SRC1), GIYD1 (SLX1), ONECUT3, CARS2, DVL-1, 2410004A20Rik, Calcineurin A (catalytic), ADAT3, GCF, SPNS2, Galpha(q)-specific peptide GPCRs, NUP35, HOXD13, PC1, RNASE11, Tubulin alpha, DNMT3A, SOX7, Creatine kinase, STK39, HEI10, USP54, FUT11, COX10, RIPK5, CENPO, GALNTL2, PLAU (UPA), Hyaluronidase, DQX1, JNK3(MAPK10), PNPH, DUB3, CHST5, PLA2G10, ADSSL1, SNRPN, REXO1, Calpain 10, HOXD3, C16orf53, Tissue kallikreins, POLE4, Cathepsin B, TEP1, Kallikrein 2, Lysmd3, PCGF1, MBD3, OLIG3, POLR3G, TYRO, Adenylate cyclase type VIII, MUC1, CHKB, PLC-beta1, TRNT1, DNA ligase IV, CaMK II gamma, AKIP, HYAL3, KLHL2, Large LDL, MED9, C6orf150, MARCH1, PPP1R3B, PRSS55, Enteropeptidase, NUAK2, Klotho, A2BP1, AGXT, CTGF, TRIML1, C2orf79, ATP8B3, MRCK, HTF9C,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 Rnase10, DEAF, Adenylate cyclase type III, NADC, MPN2, COMT, Parkin, UBE2J2, Calcineurin A (beta), Pc2, ZNF678, ZNF730, Tubulin alpha 3E, INTS11, ZNF724P, SETMAR, TRM61, BAG5, BRP44, Poly(A) polymerase, mTERFD2, POU class III, B3GT6, GPAT2, Tankyrase 1, TRAF3, OST48, ENPP3, PASK, UBC6, LASS4, 3'HEXO, Galpha(t)- specific GPCRs, ZNF717, HYAL1, FAM152A, DRIP130, Uncx, CHCHD3, ACOXL, Collagen IV, PLC-beta, ISG15, IGFBP7/8, UBE2G1, ANAPC1, CHST6 33 neuron 873 7,930E- 1,283E- 50 Contactin 4, MYH11, Smooth muscle myosin, projection 07 04 CNTN6, Neurexin beta, PLA2, PTEN, WNT3A, development CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, B3GN1, Neurexin 1-alpha, Spinophilin, CBFB/MYH11 fusion protein, MyHC, Carbohydrate sulfotransferases, Galpha(i)-specific metabotropic glutamate GPCRs, Agrin, Glypican-1, COL4A2, Dsh, WNT, PACAP, MYR8, JNK(MAPK8-10), MICAL-L2, Neurexin 1-beta, Semaphorin 4F, G- protein alpha-i family, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, CYFIP1, PLA2G10, Tissue kallikreins, Semaphorin 6D, Large LDL, Endophilin A1, CAPZ beta, Semaphorin 3F, Calcineurin A (beta), RTN4R, Collagen IV, Plexin A4 34 regulation of 362 9,400E- 1,475E- 28 Contactin 4, Complexin, Neurexin beta, PLA2, synaptic 07 04 PTEN, GluR5, Neurexin alpha, mGluR5, Neurexin transmission 1-alpha, Galpha(q)-specific metabotropic glutamate GPCRs, Complexin 2, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, NR2A, NR2, PACAP, Neurexin 1-beta, G- protein alpha-i family, G-protein alpha-i2, H-Ras, Substance P receptor, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, CaMK II gamma, Parkin, Calcineurin A (beta), Kainate receptor, RIMS2 35 multicellular 5531 1,039E- 1,585E- 203 Contactin 4, OATP8, AGTR1, FLJ22167, NOX4, organismal 06 04 APOB, CHODL, LRRTM4, BUB1, HES4, MYH11, development FHL2, Complexin, MPV17L, INTS1, Smooth muscle myosin, CD43, CNTN6, HYAL2, Neurexin beta, Dppa5, PLA2, Chapsyn-110, SPEF2, G-protein alpha-t, E2A, TXNRD2, HOXD9, PTEN, BETA-PIX, Transducin, rod-specific, WNT3A, HOXD10, Protocadherin 15, IRS-2, RING2, IFI17, LRCH4, GluR5, CHL1, PLK5, ARG1, Olfactory receptor, CXADR, Calpastatin, SIAT8D, Neurexin alpha, TLL1, PDE, E2A/HLF fusion protein, POU3F3 (BRN1), HXK2, SEZ6L2, CFC1, Carboxypeptidase H, ENPP1, mGluR5, Glis2, UBE3A (E6-AP), B3GN1, HOXD12, Neurotrimin, RRN3, LDL, DPY19L2, WNT9A, CRISPLD2, Neurexin 1-alpha, HOX11L1, TFCP2L2, Galpha(q)-specific metabotropic glutamate GPCRs, ODZ3, Spinophilin, Small LDL, HtrA2, GATA-4, Nkx6-2, KCRB, ARVCF, CBFB/MYH11 fusion protein, MyHC, AMN, PIWIL3, Tcf(Lef), Complexin 2, Carbohydrate sulfotransferases, Inversin, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, ZNF267, Agrin, Cab45, Dynein, axonemal, heavy chains, Chordin-like 1, OOEP, Glypican-1, TCF7L1 (TCF3), COL4A2, HOXD11, NR2A, HOXD4, Actifilin, FGF14, Dsh, WNT, RP1L1, IFITM3, NR2, ELKS, PACAP, MYR8, CFDP1, PDE3, A20, IL7RA, JNK(MAPK8-10), SOX1, MICAL-L2, Neurexin 1-beta, Bim, Evx2, HOXD8, HOXD1, Semaphorin 4F, G-protein alpha-i family, Sec24, IFITM2, SP-D, Foxd4L1, COL4A1, Kif2a, H- Ras, Adenylate cyclase, NCOA1 (SRC1), FGF9, ONECUT3, DVL-1, LOXL3, 2410004A20Rik, Calcineurin A (catalytic), SPNS2, NudE, Galpha(q)- specific peptide GPCRs, HOXD13, PC1, CYFIP1, DNMT3A, SOX7, Creatine kinase, Ashwin, HEI10, GPR98, PLAU (UPA), CFC1B, RAI1, MPV17, PLA2G10, HOXD3, Tissue kallikreins, Cathepsin B,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 Kallikrein 2, MBD3, OLIG3, TYRO, MUC1, CHKB, TNFAIP2, TUSC2, PLC-beta1, PMP22, DNA ligase IV, Semaphorin 3D, KIAA1715, CaMK II gamma, HYAL3, ERC2/CAST, Semaphorin 6D, Large LDL, Endophilin A1, CTGF, TRIML1, Rnase10, DEAF, CAPZ beta, Semaphorin 3F, Parkin, Calcineurin A (beta), IFITM5, Bik, RTN4R, NPAP1, mTERFD2, POU class III, Kainate receptor, Nephrocystin, Galpha(t)-specific GPCRs, ZNF717, HYAL1, Uncx, Collagen IV, PLC-beta, IGFBP7/8, Plexin A4 36 axonogenesis 616 1,261E- 1,809E- 39 Contactin 4, MYH11, Smooth muscle myosin, 06 04 CNTN6, Neurexin beta, PLA2, PTEN, WNT3A, CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, B3GN1, Neurexin 1-alpha, CBFB/MYH11 fusion protein, MyHC, Agrin, Glypican-1, COL4A2, Dsh, WNT, Neurexin 1-beta, Semaphorin 4F, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, CYFIP1, PLA2G10, Semaphorin 6D, Endophilin A1, Semaphorin 3F, Calcineurin A (beta), RTN4R, Collagen IV, Plexin A4 37 primary 10003 1,314E- 1,809E- 330 RPS28, C2orf65, PINX1, p160, PTSS2, OATP8, metabolic 06 04 AGTR1, TRMU, PDE3A, HSST2, XRCC3, NOX4, process YES, APOB, PRPF4, IMPA2, BUB1, RNPEPL1, HES4, BTEB4, FHL2, Cereblon, ERp44, INTS1, Smooth muscle myosin, DPEP3, POLE3-POLE4 complex, HDLBP, Ribonuclease H1, HYAL2, Glycogenin-1, PLA2, Chapsyn-110, SPEF2, CDC42BPB, InPP5A, G-protein alpha-t, E2A, LBX2, MSRA, GALNT13, HOXD9, CDC26, PTEN, BLK, CPA4, ADAT1, SC4MOL, Helios, Transducin, rod- specific, RNASE9, HOXD10, TTC5 (Strap), FLJ20297, FKBP15, DCTD, IRS-2, D15Wsu75e, RING2, ZNF716, VRK1, Dusp28, PDIP1, ALDP, PLK5, ARG1, OSGEP, Calpastatin, PTB2, SIAT8D, Limkain b1, TLL1, TAO2, CCDC95, POMC, 3-OST- 3B, PDE, E2A/HLF fusion protein, POU3F3 (BRN1), MRPL19, HXK2, ZNF664, MRPS9, RABL2A, PTPN18, DDX43, ABCC1, NDUFA10, Carboxypeptidase H, CCNL2, DUSP19, RNF4, ENPP1, IMP4, mGluR5, Glis2, UBE3A (E6-AP), Dexras1, B3GN1, HOXD12, SUMF1, MRPL20, RRN3, LDL, ZNF370, NS1-BP, DES1, ATHL1, RBM6, HOX11L1, CDIPT, Tex1, TFCP2L2, Galpha(q)-specific metabotropic glutamate GPCRs, Spinophilin, Small LDL, ASPHD1, HtrA2, GATA-4, FMO2, KCRB, CBFB/MYH11 fusion protein, LMNBR, PCTK3, MyHC, SIA7C, AMN, Tcf(Lef), Casein kinase I, RAI, DDX11, Carbohydrate sulfotransferases, DOM3Z, GCS1, ZNF267, NEIL2, Agrin, Dynein, axonemal, heavy chains, TTLL10, C13orf39, OOEP, PARP-2, MVP, Glypican-1, TCF7L1 (TCF3), COL4A2, DNAH10, HOXD11, Ggt6, HOXD4, ADSS, RIOK3, Casein kinase I gamma 2, FDFT1, Actifilin, SPPL2b, Dsh, PAPA1, WNT, ZNF91, SULT1A3, ELKS, ZNF378, SCOP, MEX3D, PACAP, MC-CPA, UBC7, PDE3, A20, JNK(MAPK8-10), DGCR8, SOX1, PEMT, HOXD8, CPB1, PAF49, HOXD1, APEX, PUSL1, NPC1, Kid, G-protein alpha-i family, MPP2, TINAGL1, eIF5, Sec24, PTPN20B, NAR4, SAC, MARK3, MAZ, ATF7IP2, Foxd4L1, G-protein alpha-i2, NOC2L, Metaxin 2, NRIP, Sec24C, SgK223, TPP2, H-Ras, Adenylate cyclase, C1orf25, RBM5, RNASE12, NCOA1 (SRC1), GIYD1 (SLX1), ONECUT3, CARS2, DVL-1, 2410004A20Rik, Calcineurin A (catalytic), ADAT3, GCF, SPNS2, Galpha(q)-specific peptide GPCRs, NUP35, HOXD13, PC1, RNASE11, Tubulin alpha, DNMT3A, SOX7, Creatine kinase, STK39, HEI10, USP54, FUT11, COX10, RIPK5, CENPO, GALNTL2, PLAU (UPA), Hyaluronidase, DQX1, JNK3(MAPK10), PNPH, DUB3, CHST5, PLA2G10, ADSSL1, SNRPN, REXO1, Calpain 10, HOXD3, C16orf53, Tissue kallikreins, POLE4, Cathepsin B, TEP1, Kallikrein 2, PCGF1, MBD3,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 OLIG3, POLR3G, TYRO, Adenylate cyclase type VIII, MUC1, CHKB, PLC-beta1, TRNT1, DNA ligase IV, CaMK II gamma, AKIP, HYAL3, KLHL2, Large LDL, MED9, C6orf150, MARCH1, PPP1R3B, PRSS55, Enteropeptidase, NUAK2, Klotho, A2BP1, AGXT, CTGF, TRIML1, C2orf79, ATP8B3, MRCK, HTF9C, Rnase10, DEAF, Adenylate cyclase type III, NADC, MPN2, COMT, Parkin, UBE2J2, Calcineurin A (beta), Pc2, ZNF678, ZNF730, Tubulin alpha 3E, INTS11, ZNF724P, SETMAR, TRM61, BAG5, Poly(A) polymerase, mTERFD2, POU class III, B3GT6, GPAT2, Tankyrase 1, TRAF3, OST48, ENPP3, PASK, UBC6, LASS4, 3'HEXO, Galpha(t)- specific GPCRs, ZNF717, HYAL1, FAM152A, DRIP130, Uncx, CHCHD3, ACOXL, Collagen IV, PLC-beta, ISG15, IGFBP7/8, UBE2G1, ANAPC1, CHST6 38 cell 665 1,317E- 1,809E- 41 Contactin 4, MYH11, Smooth muscle myosin, morphogenesis 06 04 CNTN6, Neurexin beta, PLA2, PTEN, WNT3A, involved in Protocadherin 15, CHL1, Olfactory receptor, neuron SIAT8D, Neurexin alpha, B3GN1, Neurexin 1-alpha, differentiation CBFB/MYH11 fusion protein, MyHC, Agrin, Glypican-1, COL4A2, Dsh, WNT, Neurexin 1-beta, Semaphorin 4F, Sec24, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, CYFIP1, PLA2G10, Semaphorin 6D, Endophilin A1, Semaphorin 3F, Calcineurin A (beta), RTN4R, Collagen IV, Plexin A4 39 positive 22 1,347E- 1,809E- 7 Neurexin beta, PTEN, Neurexin alpha, Neurexin 1- regulation of 06 04 alpha, NR2A, NR2, Neurexin 1-beta excitatory postsynaptic membrane potential 40 regulation of 78 1,356E- 1,809E- 12 Neurexin beta, PTEN, GluR5, Neurexin alpha, postsynaptic 06 04 Neurexin 1-alpha, Ionotropic glutamate receptor, membrane NR2A, NR2, PACAP, Neurexin 1-beta, Calcineurin potential A (catalytic), Kainate receptor

41 regulation of 416 1,658E- 2,158E- 30 Contactin 4, Complexin, Neurexin beta, PLA2, transmission of 06 04 PTEN, GluR5, Neurexin alpha, mGluR5, Neurexin nerve impulse 1-alpha, Galpha(q)-specific metabotropic glutamate GPCRs, Tcf(Lef), Complexin 2, Ionotropic glutamate receptor, Galpha(i)-specific metabotropic glutamate GPCRs, NR2A, NR2, PACAP, Neurexin 1-beta, G- protein alpha-i family, G-protein alpha-i2, H-Ras, Substance P receptor, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, Tissue kallikreins, CaMK II gamma, Parkin, Calcineurin A (beta), Kainate receptor, RIMS2 42 neuron 489 2,165E- 2,687E- 33 Contactin 4, MYH11, Smooth muscle myosin, projection 06 04 CNTN6, Neurexin beta, PLA2, WNT3A, CHL1, guidance Olfactory receptor, SIAT8D, Neurexin alpha, B3GN1, Neurexin 1-alpha, CBFB/MYH11 fusion protein, MyHC, Agrin, Glypican-1, COL4A2, Dsh, WNT, Neurexin 1-beta, Semaphorin 4F, Foxd4L1, COL4A1, H-Ras, DVL-1, Galpha(q)-specific peptide GPCRs, PLA2G10, Semaphorin 6D, Endophilin A1, Semaphorin 3F, Collagen IV, Plexin A4 43 axon guidance 489 2,165E- 2,687E- 33 Contactin 4, MYH11, Smooth muscle myosin, 06 04 CNTN6, Neurexin beta, PLA2, WNT3A, CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, B3GN1, Neurexin 1-alpha, CBFB/MYH11 fusion protein, MyHC, Agrin, Glypican-1, COL4A2, Dsh, WNT, Neurexin 1-beta, Semaphorin 4F, Foxd4L1, COL4A1, H-Ras, DVL-1, Galpha(q)-specific peptide GPCRs, PLA2G10, Semaphorin 6D, Endophilin A1, Semaphorin 3F, Collagen IV, Plexin A4 44 axon 681 2,389E- 2,897E- 41 Contactin 4, MYH11, Smooth muscle myosin, development 06 04 CNTN6, Neurexin beta, PLA2, PTEN, WNT3A, CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, B3GN1, Neurexin 1-alpha, CBFB/MYH11 fusion protein, MyHC, Carbohydrate sulfotransferases, Agrin, Glypican-1, COL4A2, Dsh, WNT, Neurexin 1-

Downloaded From: https://jamanetwork.com/ on 09/26/2021 beta, Semaphorin 4F, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, CYFIP1, PLA2G10, Semaphorin 6D, Large LDL, Endophilin A1, Semaphorin 3F, Calcineurin A (beta), RTN4R, Collagen IV, Plexin A4 45 neuron 682 2,477E- 2,938E- 41 Contactin 4, MYH11, Smooth muscle myosin, projection 06 04 CNTN6, Neurexin beta, PLA2, PTEN, WNT3A, morphogenesis CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, B3GN1, Neurexin 1-alpha, CBFB/MYH11 fusion protein, MyHC, Agrin, Glypican-1, COL4A2, Dsh, WNT, MYR8, Neurexin 1-beta, Semaphorin 4F, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL- 1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, CYFIP1, PLA2G10, Tissue kallikreins, Semaphorin 6D, Endophilin A1, Semaphorin 3F, Calcineurin A (beta), RTN4R, Collagen IV, Plexin A4 46 cell 1936 2,817E- 3,268E- 87 Contactin 4, PDE3A, MYH11, FHL2, Smooth muscle development 06 04 myosin, CNTN6, Neurexin beta, PLA2, Chapsyn- 110, G-protein alpha-t, E2A, HOXD9, PTEN, Transducin, rod-specific, WNT3A, HOXD10, Protocadherin 15, CHL1, Olfactory receptor, CXADR, SIAT8D, Neurexin alpha, PDE, E2A/HLF fusion protein, B3GN1, Neurotrimin, DPY19L2, Neurexin 1-alpha, Spinophilin, HtrA2, GATA-4, Nkx6-2, CBFB/MYH11 fusion protein, MyHC, Tcf(Lef), Carbohydrate sulfotransferases, Galpha(i)- specific metabotropic glutamate GPCRs, Agrin, Glypican-1, TCF7L1 (TCF3), COL4A2, Dsh, WNT, RP1L1, PACAP, MYR8, PDE3, JNK(MAPK8-10), SOX1, MICAL-L2, Neurexin 1-beta, Bim, Semaphorin 4F, G-protein alpha-i family, Sec24, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL- 1, LOXL3, Calcineurin A (catalytic), Galpha(q)- specific peptide GPCRs, CYFIP1, HEI10, GPR98, PLA2G10, Tissue kallikreins, TUSC2, PLC-beta1, DNA ligase IV, Semaphorin 6D, Large LDL, Endophilin A1, Rnase10, DEAF, CAPZ beta, Semaphorin 3F, Parkin, Calcineurin A (beta), RTN4R, POU class III, MYOZ1, Nephrocystin, Collagen IV, PLC-beta, Plexin A4 47 regulation of 70 3,015E- 3,423E- 11 Neurexin beta, PTEN, GluR5, Neurexin alpha, excitatory 06 04 Neurexin 1-alpha, Ionotropic glutamate receptor, postsynaptic NR2A, NR2, Neurexin 1-beta, Calcineurin A membrane (catalytic), Kainate receptor potential 48 cell projection 846 3,925E- 4,364E- 47 Contactin 4, FLJ22167, MYH11, Smooth muscle morphogenesis 06 04 myosin, CNTN6, Neurexin beta, PLA2, SPEF2, PTEN, WNT3A, Protocadherin 15, CHL1, Olfactory receptor, SIAT8D, Neurexin alpha, RABL2A, B3GN1, Neurexin 1-alpha, C16orf63, CBFB/MYH11 fusion protein, MyHC, Agrin, Glypican-1, COL4A2, Dsh, WNT, SPAG16, MYR8, Neurexin 1-beta, Semaphorin 4F, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, DVL-1, Calcineurin A (catalytic), Galpha(q)-specific peptide GPCRs, CYFIP1, PLA2G10, Tissue kallikreins, Semaphorin 6D, Endophilin A1, Semaphorin 3F, Calcineurin A (beta), RTN4R, Collagen IV, Plexin A4 49 positive 36 4,704E- 5,123E- 8 Neurexin beta, PTEN, Neurexin alpha, Neurexin 1- regulation of 06 04 alpha, Ionotropic glutamate receptor, NR2A, NR2, membrane Neurexin 1-beta potential 50 single-organism 4750 4,806E- 5,130E- 176 Contactin 4, OATP8, AGTR1, PDE3A, FLJ22167, developmental 06 04 NOX4, APOB, CHODL, BUB1, MYH11, FHL2, process MPV17L, INTS1, Smooth muscle myosin, CD43, CNTN6, HYAL2, Neurexin beta, PLA2, Chapsyn- 110, SPEF2, G-protein alpha-t, E2A, TXNRD2, MSRA, HOXD9, PTEN, Transducin, rod-specific, WNT3A, HOXD10, Protocadherin 15, IRS-2, RING2, IFI17, CHL1, ARG1, Olfactory receptor, CXADR, Calpastatin, SIAT8D, Neurexin alpha, PDE, E2A/HLF fusion protein, POU3F3 (BRN1), HXK2, SEZ6L2, RABL2A, CFC1, Carboxypeptidase H,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 UBE3A (E6-AP), B3GN1, HOXD12, Neurotrimin, RRN3, LDL, DPY19L2, WNT9A, CRISPLD2, Neurexin 1-alpha, C16orf63, HOX11L1, Spinophilin, Small LDL, HtrA2, GATA-4, Nkx6-2, KCRB, CBFB/MYH11 fusion protein, MyHC, Tcf(Lef), Casein kinase I, Carbohydrate sulfotransferases, Inversin, Ionotropic glutamate receptor, Galpha(i)- specific metabotropic glutamate GPCRs, Agrin, Cab45, Chordin-like 1, OOEP, Glypican-1, TCF7L1 (TCF3), COL4A2, HOXD11, NR2A, HOXD4, Actifilin, Dsh, WNT, RP1L1, IFITM3, NR2, SPAG16, PACAP, MYR8, PDE3, A20, IL7RA, JNK(MAPK8- 10), SOX1, MICAL-L2, Neurexin 1-beta, Bim, Evx2, HOXD8, HOXD1, APEX, Semaphorin 4F, G-protein alpha-i family, Sec24, IFITM2, SP-D, Foxd4L1, COL4A1, H-Ras, Adenylate cyclase, NCOA1 (SRC1), FGF9, ONECUT3, DVL-1, LOXL3, Calcineurin A (catalytic), SPNS2, NudE, Galpha(q)- specific peptide GPCRs, HOXD13, PC1, CYFIP1, DNMT3A, SOX7, Creatine kinase, Ashwin, HEI10, GPR98, PLAU (UPA), CFC1B, MPV17, PLA2G10, Calpain 10, HOXD3, Tissue kallikreins, Cathepsin B, Kallikrein 2, MBD3, TYRO, MUC1, CHKB, TNFAIP2, TUSC2, PLC-beta1, PMP22, DNA ligase IV, KIAA1715, Semaphorin 6D, Large LDL, Endophilin A1, Klotho, CTGF, Rnase10, DEAF, CAPZ beta, Semaphorin 3F, Parkin, Calcineurin A (beta), Bik, RTN4R, mTERFD2, POU class III, MYOZ1, Nephrocystin, Galpha(t)-specific GPCRs, HYAL1, Uncx, Collagen IV, PLC-beta, IGFBP7/8, Plexin A4 GO process: GO process indicates a biological process, as defined by the Gene Ontology (GO) Consortium (http://geneontology.org). The 29 significantly enriched GO process with a role in neurogenesis, cognition, learning, memory and behavior are emboldened. Total: total number of network objects (proteins and interactions) that are included (i.e. have a function) in the listed GO process. FDR: false discovery rate. In Data: number of network objects encoded by genes embedded in the deletion identified in EGCUT belonging to the listed GO process. The entire list of 642 embedded genes is provided below. Network objects: catalog of network objects in the current data set used by Thomson Reuters MetaCore™ for mapping on functional ontologies to find significant enrichments (see eMethods for more details)

Protein-coding genes encompassed by rare deletions used as a seed for creating a list of network objects by Thomson Reuters MetaCore™

ABCC1, ABHD13, ABHD17A, AC006455.1, AC006547.14, AC009365.3, AC010760.1, AC011298.1, AC012360.1, AC012360.2, AC013269.5, AC013469.1, AC016745.1, AC022400.2, AC073188.1, AC079612.1, AC092811.1, AC093802.1, AC104809.3, AC104841.2, AC110619.2, AC138393.1, AC140481.2, AC142381.1, ACAP2, ACAP3, ACOXL, ADAT1, ADAT3, ADCY10, ADCY3, ADCYAP1, ADSS, AF131215.5, AGAP4, AGAP5, AGRN, AGTR1, AGXT, AL049840.1, AL645608.1, AL645608.2, ALAD, AMN, ANAPC1, ANKMY1, ANKRD10, ANKRD36C, ANKRD62, ANKRD65, ANO7, ANO9, ANXA11, APEX1, APOB, APOPT1, AQP12A, AQP12B, ARG1, ARHGEF4, ARHGEF7, ARVCF, ASPHD1, ATAD3B, ATAD3C, ATF7IP2, ATHL1, ATP8B3, AUP1, AURKAIP1, B3GALT6, B4GALNT4, BAG5, BCL2L11, BIVM, BIVM-ERCC5, BLK, BOLA2, BSPRY, BTBD2, BTG3, BUB1, C10orf55, C14orf64, C16orf45, C16orf54, C18orf8, C1orf101, C1orf159, C1orf170, C21orf37, C21orf91, C2orf49, C2orf54, C8orf12, C8orf49, C8orf74, CAMK2G, CAPN10, CAPSL, CARKD, CARS2, CAST, CBWD2, CCDC115, CCDC142, CCDC168, CCDC92, CCNB1IP1, CCNL2, CCSER1, CCZ1B, CD320, CDC26, CDC42BPB, CDH12, CDIPT, CDK18, CDRT15, CDRT4, CENPO, CERS4, CFC1, CFC1B, CFDP1, CHCHD1, CHCHD3, CHL1, CHODL, CHST5, CHST6, CKB, CLDN23, CNIH3, CNIH4, CNTN4, CNTN6, COL4A1, COL4A2, COMT, COX10, CPA3, CPB1, CPE, CPLX2, CPSF3L, CRBN, CRISPLD1, CRISPLD2, CSMD1, CSNK1G2, CTAGE9, CTGF, CTSB, CXADR, CYFIP1, CYP4F31P, DCAF6, DCTD, DDX43, DEFB130, DEFB134, DEFB135, DEFB136, DEGS1, DESI2, DGCR6L, DGCR8, DKFZP547L112, DLG2, DNAH10, DNAH10OS, DNAH14, DNAJC27, DNMT3A, DOK1, DPPA5, DPY19L2, DQX1, DSTYK, DTNB, DUSP19, DUSP28, DVL1, EFR3B, EIF5, ELTD1, ENPP1, ENPP3, EPS8, ERI1, ERP44, EVA1A, EVX2, EXOC3L4, FAM101A, FAM132A, FAM153B, FAM155A, FAM167A, FAM168B, FAM174A, FAM218A, FAM21C, FAM228A, FAM228B, FAM25E, FAM86B1, FAM86B2, FBN3, FBXO28, FDFT1, FGF14, FGF9, FHL2, FKBP15, FMO2, FMO3, FMO6P, FOPNL, FOXD4L1, FRG2C, FUT11, GABARAPL2, GALNT13, GATA4, GCFC2, GGT6, GLTPD1, GNAI2, GNAT1, GOLGA6L1, GOLGA6L2, GOLGA8I, GOLGA8S, GPAT2, GPC1, GPR35, GPR45, GPR98, GRIK1, GRIN2A, GRM5, GRM7, GYG1, HDHD3, HDLBP, HEPHL1, HES4, HIRIP3, HK2, HOXD1, HOXD10, HOXD11, HOXD12, HOXD13, HOXD3, HOXD4, HOXD8, HOXD9, HRAS, HS3ST3B1, HTRA2, HYAL1, HYAL2, HYAL3, IFITM1, IFITM2, IFITM3, IFITM5, IFRD2, IKZF2, IL5RA, IL7R, IMP4, IMPA2, ING1, INO80B, INO80E, INPP5A, INTS1, INVS, IRS2, ISG15, ITSN2, IVNS1ABP, JMJD4, KANK3, KCNQ5, KCTD13, KDELC1, KHDC1, KHDC1L, KHDC3L, KIAA0430, KIAA0513, KIAA1432, KIAA1671, KIAA1715, KIF1A, KIF22, KL, KLC1, KLF16, KLHDC8A, KLHL17, KLHL2, KLHL33, LBR, LBX2, LEMD1, LIG4, LIMS3, LIMS3L, LINC00346, LOXL3, LRRC56, LRRN1, LRRTM4, LSMEM2, LST3, LUZP2, LYSMD3, M1AP, MALL, MAPK10, MARCH1, MARK3, MAZ, MB21D1, MBD3, MBLAC2, MED23, MED9, MEI4, METTL21C, MEX3D, MFHAS1, MICALL2, MICU2, MMRN1, MOGS, MPC2, MPV17L, MPZL1, MROH9, MRPL19, MRPL20, MRPL53, MRPS9, MSMO1, MSRA, MSS51, MTERFD2, MTMR9, MTX2, MVP, MXRA8, MYBBP1A, MYEOV2, MYH11, MYO16, MYOZ1, MZT2B, NAT6, NCOA1,

Downloaded From: https://jamanetwork.com/ on 09/26/2021 NDE1, NDST2, NDUFA10, NDUFA7, NEIL2, NIPA1, NIPA2, NKX6-2, NLRP6, NOC2L, NOMO1, NOX4, NPAP1, NPC1, NPHP1, NPIPA1, NPIPA2, NPIPA3, NPIPA5, NPIPB11, NRXN1, NTAN1, NTM, NUAK2, NUP35, NVL, OLIG3, ONECUT3, OOEP, OR11H4, OR2A4, OR4M2, OR4N4, OR6B2, OR6B3, OSGEP, OTOS, PAGR1, PANX1, PAPOLA, PARK2, PARP2, PASK, PCDH15, PCDH7, PCGF1, PCSK1, PDCD1LG2, PDE3A, PDXDC1, PEMT, PFN4, PHLPP1, PINX1, PIWIL3, PKP3, PLA2G10, PLAC9, PLAU, PLCB1, PLEKHB2, PLEKHN1, PLK5, PLXNA4, PMP22, PNP, POLE4, POLR3G, POM121L12, POMC, POTEB, POTEE, POTEI, POTEJ, POU3F3, PPP1R3B, PPP1R7, PPP3CB, PRPF4, PRR21, PRRT2, PRSS38, PRSS55, PTBP2, PTDSS2, PTPN18, PTPN20A, PTRHD1, PUSL1, QPRT, RAB20, RABL2A, RAI1, RANBP1, RASD1, RBFOX1, RBM5, RBM6, RCSD1, REXO1, RGPD5, RGPD6, RIMS2, RIOK3, RNASE10, RNASE11, RNASE12, RNASE9, RNF183, RNF2, RNF223, RNH1, RNPEPL1, RP11-1021N1.1, RP11-10A14.4, RP11-204N11.1, RP11-231C14.4, RP11-257K9.8, RP11-297N6.4, RP11-345J4.3, RP11-345J4.5, RP11-467N20.5, RP11-481A20.11, RP11-507M3.1, RP11-574K11.31, RP11-65D24.2, RP11- 73M18.2, RP11-77K12.1, RP11-77K12.7, RP11-826N14.2, RP1L1, RP4-758J18.2, RPS28, RRN3, RSPH10B2, RTKN, RTN4R, SAMD11, SCAMP4, SCNN1D, SDF4, SEC24C, SEMA3D, SEMA3F, SEMA4F, SEMA6D, SETMAR, SEZ6L2, SFTPD, SGK223, SGSM1, SH3GL2, SIGIRR, SLC16A7, SLC31A1, SLC31A2, SLC35F5, SLC35G5, SLCO1B3, SLCO1B7, SLCO1C1, SLX1B, SMPD4, SMTNL2, SNAP47, SNED1, SNRPN, SNURF, SOX1, SOX7, SPACA7, SPAG16, SPEF2, SPN, SPNS2, SPNS3, ST6GALNAC3, ST8SIA4, STARD13, STX17, SULT1A4, SUMF1, SWT1, SYNPO2L, TACR1, TANGO2, TAOK2, TAS1R3, TCF3, TDRD15, TEKT3, TENM3, TEP1, TEX29, TEX30, TGFBRAP1, THOC3, TLL1, TLX2, TMCC2, TMEM132C, TMEM170A, TMEM192, TMEM211, TMEM219, TMEM231, TMEM241, TMEM254, TMEM55B, TMEM88B, TMPRSS15, TMX4, TNFAIP2, TNFAIP3, TNFRSF18, TNFRSF4, TNFSF13B, TNKS, TP53TG3D, TPP2, TRAF3, TRIM60, TRIM61, TRIML1, TRMT1L, TRMT2A, TRMT61A, TRNT1, TTC31, TTC40, TTC5, TTLL10, TUBA3E, TUBGCP3, TUBGCP5, TUSC2, TVP23C, TVP23C-CDRT4, TXNRD2, TYR, UBE2G1, UBE2J2, UBE3A, UGT3A1, UNCX, UQCR11, USP17L2, USP54, VRK1, VWA1, WBP1, WDR26, WDR31, WNT3A, WNT9A, WWC2, XKR6, XRCC3, XXYLT1, YES1, ZCCHC2, ZDHHC20, ZDHHC7, ZDHHC8, ZFYVE21, ZG16, ZNF267, ZNF664, ZNF678, ZNF705D, ZNF716, ZNF717, ZNF724P, ZNF730, ZNF91, ZSWIM8

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eFigure 1. Diagnoses reported in the EGCUT participants according to the WHO ICD-10 classification

98.3% of recruited EGCUT individuals reported to have suffered or currently suffer from at least one disease. Altogether participants were diagnosed for a total of 386,247 illnesses/diseases, i.e. on average 7.4 different diagnoses per individual. 1.5% (792) of participants have confirmed that they have never had any diseases, while 0.47% (243) are not aware of their diseases. The data were extracted from the data freeze made upon recruitment of 51,869 participants.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eFigure 2. Multidimensional scaling analysis of EGCUT population structure

(A)

(B)

Downloaded From: https://jamanetwork.com/ on 09/26/2021

To exclude the possibility that the EGCUT cohort could be affected by hidden population stratification, multidimensional scaling (MDS) analysis was performed. Autosomal SNPs that passed quality control from a set of 8,000 randomly selected EGCUT samples genotyped using Illumina HumanOmniExpress were used to calculate the pairwise identical by state (IBS) distance (see eMethods). The first two MDS dimensions are plotted against one another. (A) Segregation by CNVs: Individuals identified as carriers of a rare deletion or duplication in the current study are indicated by dots colored in red and green, respectively. Non-carriers are in grey. In panel (B) Segregation by ethnicity: Estonian individuals are indicated in light blue, Russian in purple, Ukrainian in magenta, Belarusian in light pink, Finnish in yellow, Jew/Israelite in orange, Tatar in coral, German in blue, Latvian in black, Polish in brown, Lithuanian in green yellow and other minorities in cyan.

Downloaded From: https://jamanetwork.com/ on 09/26/2021 eFigure 3: Assessment of CNV deleteriousness

Comparison of achieved education levels in the assessed general population (EGCUT) with that of carriers of deletions encompassing 2-10 or more than 10 genes and duplications including more than 10 genes (all protein- and non- coding combined). The numbers of contributing data in each category are indicated below. Education levels are coded according to the Estonian education curriculum: 1 - less than primary; 2 - primary; 3 – basic; 4 – secondary; 5 – professional higher/college; 6 – university/academic degree; 7 – scientific degree (see eMethods for details). Note that the value equals 0% in the groups of “less than primary education” and “scientific degree” of deletion carriers with ≥11 encompassed genes and in the group of “less than primary education” of duplication carriers with ≥11 encompassed genes.

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