Aia Elise Jønch , Elise Douard , Clara Moreau , Anke Van Dijck , Marzia

Home , Hypochondroplasia, Hypogammaglobulinemia, OR2C3, OR2G2, OR2G3, OR2G6

Supplementary material J Med Genet

Jønch et al.

ESTIMATING THE EFFECT SIZE OF THE 15Q11.2 BP1-BP2 DELETION AND ITS CONTRIBUTION TO NEURODEVELOPMENTAL SYMPTOMS: RECOMMENDATIONS FOR PRACTICE

Aia Elise Jønch1,2,3, Elise Douard4,5, Clara Moreau4,5, Anke Van Dijck6, Marzia Passeggeri7, R. Frank Kooy6, Jacques Puechberty8, Carolyn Campbell9, Damien Sanlaville10,11, Henrietta Lefroy12, Sonia Richetin7, Aurélie Pain7,13, David Genevieve8,14,15, Usha Kini12,16, Cédric Le Caignec17,18, James Lespinasse19, Anne-Bine Skytte20,21, Bertrand Isidor17, Christiane Zweier22, Jean-Hubert Caberg23, Marie-Ange Delrue4,5, 15q11.2 Working Group, Anders Bojesen24, Helle Hjalgrim25, Charlotte Brasch-Andersen1,2, Emmanuelle Lemyre4,5, Lilian B. Ousager1,2* & Sébastien Jacquemont4,5,7*

Supplementary information

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Table of Contents

Members of the 15q11.2 working group ...... 5 Supplementary Materials and Methods ...... 7 S1.1. Participants and Data Sources ...... 7

S1.2. Cognitive Assessments ...... 9

S1.3. Microarray platforms ...... 9

S1.4. Additional pathogenic variants ...... 9

S1.5. Conversion of odds-ratios to a shift in IQ ...... 10

S1.6. Logistic Regression Models ...... 11

S1.7. The Probability of Loss-of-Function Intolerance (pLI) ...... 12

Supplementary Results ...... 13 S1.1. Neurological symptoms ...... 13

S1.2. Magnetic resonance image (MRI) ...... 13

S1.3. Major Malformation ...... 13

S1.4. Major Medical Conditions ...... 14

S1.5. Dysmorphism ...... 14

Supplementary Figures ...... 15 Figure S1. Distribution of CNVs based on pLI score and classification in the SJCHU database ...... 15

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Figure S2. Estimation of the probability to be de novo in function of the pLI score of a CNV ...... 17

Figure S3. Contour-shaded funnel plot of 20 15q11.2 deletion studies included in our meta-analyses ...... 18

Figure S4. Contour-shaded funnel plot of 7 15q11.2 duplication studies included in our meta-analyses ...... 19

Figure S5. Additional CNVs detected in 15q11.2 deletion and duplication probands from the clinically referred group and their

distribution by size (A), number of genes (B) and pLI score (C) ...... 20

Supplementary Tables ...... 22 Table S1. Characteristics of published 15q11.2 deletion studies investigating neurodevelopmental disorders and congenital heart

disease ...... 22

Table S2. Characteristics of published 15q11.2 duplication studies investigating neurodevelopmental disorders ...... 25

Table S3. Cognitive and behavioral results for 15q11.2 CNV carriers from the clinically referred group ...... 26

Table S4. Comparing frequencies of additional pathogenic CNVs in 15q11.2 deletion and duplication carriers from the clinically

referred group ...... 28

Table S5. Characteristics of additional pathogenic CNVs detected in 15q11.2 deletion and duplication probands from the

clinically referred group ...... 29

Table S6. Additional genetic variants identified in 15q11.2 deletion and duplication probands from the clinically referred group

...... 45

Table S7. Transmission and de novo frequency in previous published 15q11.2 deletion studies and case series ...... 47

Table S8. Transmission and de novo frequency of the 15q11.2 CNVs in the DECIPHER database ...... 53

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Table S9. Comparing frequencies of ASD in 15q11.2 deletion and duplication probands from the clinically referred group ...... 54

Table S10. Comparing frequencies of epilepsy in 15q11.2 CNV carriers from the clinically referred group ...... 55

Table S11. Neurological features in 15q11.2 deletion carriers from the clinically referred group according to ascertainment ...... 56

Table S12. Neurological features in 15q11.2 duplication carriers from the clinically referred group according to ascertainment 58

Table S13. Comparing frequencies of congenital heart disease in 15q11.2 CNV carriers from the clinically referred group ...... 60

Table S14. Malformation and medical conditions in 15q11.2 deletion carriers from the clinically referred group according to

ascertainment ...... 61

Table S15. Malformation and medical conditions in 15q11.2 duplication carriers from the clinically referred group according to

ascertainment ...... 64

Table S16. Comparing frequencies of ID in 15q11.2 deletion and duplication probands from the clinically referred group ...... 67

Supplementary References ...... 68

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Members of the 15q11.2 working group

Andrieux Joris, Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France; Barnicoat Angela, Department of Clinical Genetics, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom; Blanchet Patricia, Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France; Blesson Sophie, Service de Génétique, CHRU de Tours, Tours, France; Bütschi Florence Niel, Service de Médecine Génétique, CHUV Lausanne, Lausanne Switzerland; Campeau Philippe M., Department of Pediatrics, University of Montreal, Montreal, QC, Canada, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada; Chelloug Nora, Laboratoire Cytogénétique constitutionnelle, CHRU de Tours, Tours, France; Debray François-Guillaume, Service de Génétique Humaine, CHU de Liège, Université de Liège, Liège, Belgium; Fellmann Florence, Service de Médecine Génétique, CHUV Lausanne, Lausanne Switzerland; Ferrarini Alessandra, Division of Pediatrics, San Giovanni Hospital, Bellinzona, Switzerland; Gibbons Richard, University of Oxford, Medical Sciences Division, Oxford, United Kingdom; Gregersen Pernille Axel, Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark; Hoyer Juliane, Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Hüffmeier Ulrike, Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Kjelgaard Ditte, Danish Epilepsy Center, Filadelfia, Dianalund, Denmark; Krumbiegel Mandy, Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Lebon Sébastien, Pediatric Neurology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland; Lesca Gaetan, Service de Génétique, Hospices Civils de Lyon, Lyon, France, Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR5292, GENDEV Team, Lyon, France; Marignier Stéphanie, Centre de Référence, Déficiences Intellectuelles de Causes Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Mercier Sandra, CHU Nantes, Service de Génétique Médicale, Nantes, France; Michaud Jacques, Division of Medical Genetics, Department of Pediatrics, CHU Saint-Justine, Université de Montréal, Québec, Canada, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Québec, Canada; Mitchell Grant, Division of Medical Genetics, Department of Pediatrics, CHU Saint-Justine, Université de Montréal, Québec, Canada; Mortemousque Isabelle, Service de Génétique, CHRU de Tours, Tours, France; Møller Rikke S., Danish Epilepsy Center, Filadelfia, Dianalund, Denmark, Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark; Nizon Mathilde, CHU Nantes, Service de 5

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Génétique Medicale, Nantes, France; Pierquin Genevieve, Centre de Génétique Humaine, CHU de Liège, Liège, Belgium; Pilekær Sørensen Kristina, Department of Clinical Genetics, Odense University Hospital, Denmark; Price Sue, Department of Clinical Genetics, Notrhampton General Hospital, Northampton, United Kingdom; Pujol Pascal H., Département de Génétique Médicale, Oncogénétique Clinique, CHU de Montpellier, Hôpital Arnaud De Villeneuve, Montpellier, France; Ramaekers Vincent, Neuropédiatrie et maladies Neurométaboligueq, CHU de Liège, Liège, Belgium; Raynaud Martine, Laboratoire de Génétique Moléculaire, CHRU de Tours, Tours, France; Reis André, Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Rossi Massimiliano, Service de Génétique, Hospices Civils de Lyon, Bron, France, and Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR5292, GENDEV Team, Bron, France; Sarda Pierre, Service de Génétique Médicale, CHU de Montpellier, Hôpital Arnaud De Villeneuve, Montpellier, France; Stanzial Franco, Servizio di Consulenza Genetica, Centro Provinciale di Coordinamento della Rete delle Malattie Rare, Azienda Sanitaria dell'Alto-Adige, Bolzano, Italy; Stewart Helen, Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; Svaneby Dea, Department of Clinical Genetics, Sygehus Lillebaelt, Vejle, Denmark; Theil Christian T., Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen- Nürnberg, Erlangen, Germany; Till Marianne, Centre de référence des anomalies du développement, Service de Génétique Hospices Civils de Lyon, Bron, France; Trakadis Yannis, Department of Medical Genetics, McGill University Health Centre, Montréal, Québec, Canada; Ville Dorothée, Centre de référence, Déficiences Intellectuelles de causes rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Vonwill Sandrine, Service de Génétique, CHRU de Tours, Tours, France, INSERM UMR_U930, Faculté de Médecine, Université de Tours, Tours, France; Wilkie Andrew, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom; Wiessner Antje, Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen- Nürnberg, Erlangen, Germany.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Supplementary Materials and Methods S1.1. Participants and Data Sources

391 deletion and 214 duplication carriers were ascertained through different sites for the clinically referred group. Data were collected

retrospectively and retained anonymously in our data management system into the following main categories: prenatal period, birth

parameters, development, behavior, therapy, evaluations, diagnosis, medical and/or neurological examination, malformations,

dysmorphism, paraclinical investigations as EEG, MRI and ultrasound, surgery, treatment, growth and family history.

Saint-Justine University Hospital (SJCHU) Montréal, Canada ascertainment

Data on 175 probands (98 deletion, 77 duplication) came from the neurodevelopmental array database at SJCHU (n=14463). In addition 45

participant carriers (32 deletion, 13 duplication) came from the same array database or were recruited directly from the genetic clinics.

Medical and psychiatric diagnosis was obtained from available medical records, clinician reports or from a parent.

Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland ascertainment

Data from 143 participants (87 deletion, 56 duplication) originating from France, Belgium, Denmark, Germany, Italy, the Netherlands,

Switzerland and the United Kingdom were obtained by completion of a questionnaire by the referring clinician.

Odense University Hospital (OUH) Denmark ascertainment

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. 28 participants (13 deletion, 15 duplication) from Denmark were recruited for the study and underwent full clinical evaluation on site by

the same investigator (AEJ). Medical and psychiatric history was collected, anthropometrics measured, and eventual dysmorphic features

described. These participants were identified with help from the Danish Cytogenetic Central Register (DCCR),1 and the Departments of

Clinical Genetics in Denmark.

Unique and 15q11.2 Duplication Network ascertainment

29 participants were included online (11 deletion, 18 duplication) from two different organizations: Unique the U.K.-based rare

chromosome disorder support group (https://www.rarechromo.org/), and the US-based 15q11.2 duplication network (Facebook group). The

information officer from Unique and the founders of the duplication network informed their contacts and members, respectively, about the

study, and encouraged them to contact the study teams if they wanted to participate. Families provided clinical information by completion

of questionnaires and/or copies of medical records.

Previous literature studies

We also included 185 cases (150 deletions and 35 duplications) from previously published studies in the literature.2-18 We only used

literature cases with enough information to distinguish them from other cases, such as information about ascertainment, gender (most

cases), age, inheritance and additional clinical information.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. S1.2. Cognitive Assessments

For the overall cognitive functioning either Wechsler Intelligence Scales, Wechsler abbreviated scale of intelligence (WPPSI-III, WPPSI-

R, WPPSI-IV, WISC-IV, WISC-R, WAIS-III, WAIS-IV),19-25 or other ability scales (Leiter-R, SON-R, RIAS)26-28 had been used to obtain

Full Scale Intelligence Quotient (FSIQ), Verbal Intelligence Quotient (VIQ), and Non-Verbal Intelligence Quotient (NVIQ). Results are

presented in table S3.

S1.3. Microarray platforms

The 15q11.2 deletions and duplications as well as additional CNVs were identified through various procedures: a) CGH array with Agilent

(Santa Clara, CA) 44K, 60K, 105K, 180K, and 244K; b) Affymetrix genotyping arrays (Santa Clara, CA) 250K, 750K; c) Affymetrix 2.7,

6.0 SNP arrays; d) QPCR; e) MLPA; f) FISH; g) whole exome sequencing (one patient).

S1.4. Additional pathogenic variants

Presence of additional genetic variants was not an exclusion criterion in this study. Additional pathogenic CNVs were identified in 27

deletion and 13 duplication carrying probands as well as in 4 deletion and 4 duplication carrier relatives table S4 and S5 (data are not

shown for relative carriers in table S4). For the interpretation of CNVs we used the standards and guidelines from the American College of

Medical Genetics.29 The classification of CNVs as clinical significant, unknown (VOUS) or benign was carried out by two independent

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. raters: one geneticist (AEJ), and one specialist in chromosomal microarray and certified clinical laboratory geneticist (CBA), whenever the

interpretation of the CNV(s) was not part of the data collected. We were unable to classify 26 additional CNVs from 13 15q11.2 deletion

and 10 duplication carrying probands ascertained through the literature 3 14 due to missing information concerning the boundaries. These 26

additional CNVs were therefore not included in any analysis. Single nucleotide variants (SNVs) and structural chromosomal

rearrangements observed in 13 deletion and 5 duplication carrying probands are presented in table S6. 10 of these 18 SNVs and

chromosomal rearrangements were considered pathogenic (n=9) or likely pathogenic (n=1).

S1.5. Conversion of odds-ratios to a shift in IQ

The following model is adapted from Huguet and colleagues (2018).30 In a simulation study the OR corresponding to a continuum of

plausible values of the IQ shift between carriers and non-carriers of the CNV of interest was computed. This simulation study was made

under the following assumptions: (i) mean of IQ of non-carriers is equal to 100, (ii) mean of IQ of carriers is equal to 100-shift, (iii) the SD

of IQ for both carriers and non-carriers is equal to 15, (iv) all subjects having an IQ ≤ threshold are referred in clinic (clinical population)

whereas all subjects having an IQ > threshold are controls. Three values of threshold of IQ from which subjects are referred in clinic were

considered (2 SD = 70 points, 1.75 SD = 73.75 points and 1.5 SD = 77.5 points). The procedure of simulation, for each threshold and for

each shift from 0.5 to 50 (with 0.1 increments) is as follow:

1) IQ was generated of a sample of 500 non-carriers of the CNV of interest using normal distribution, with mean 100 and SD 15;

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. This model consists in performing a binary logistic model in order to estimate the probability to be de novo as a function of the sum of pLI

scores for the CNV observed. The dependent variable is the transmission mode of the CNV whereas the independent variable is the sum of

pLI scores of the CNV. If a CNV is not in an exonic location, the total pLI score is 0. Only CNVs ≥ 50Kb are included in the analyses

leading to a non-observation of 0 < total CNVs size < 50Kb. This gap could bias the estimation of the effect of the total pLI score of the

CNV.

S1.7. The Probability of Loss-of-Function Intolerance (pLI)

pLI is a metric that rank human genes according to their probability of being intolerant to loss-of-function (LoF) mutations. The metric

compare the observed and expected number of Protein Truncating Variant (PTV) counts per gene to separate the genes into one of three

categories: i) LoF tolerant (pLI ≤0.1 or observed ~ expected) ii) heterozygous (recessive) LoFs are tolerated (observed ≤ 50% of expected)

iii) LoF intolerant (haploinsufficient) (pLI ≥0.9 or observed < 10% of expected). The closer the pLI score is to 1 the more likely the

transcript is LoF intolerant and falls into the haploinsufficient category. The pLI analysis is based on the genetic variations observed in

60,706 healthy individuals of diverse ethnicity by the Exome Aggregation Consortium (ExAC).34

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Supplementary Results S1.1. Neurological symptoms

Peripheral hypotonia 8.2% (32/391), motor dyspraxia 3.3% (13/391), coordination problems 3.3% (13/391) and ataxia 2.8% (11/391) are

the most frequent neurological symptoms reported in deletion carriers (table S11). In the reciprocal duplication, similar frequencies are

reported for all of these neurological symptoms: peripheral hypotonia 11.7% (25/214), motor dyspraxia 1.4% (3/214), coordination

problems 4.7% (10/214), and ataxia 1.9% (4/214) (table S12).

S1.2. Magnetic resonance image (MRI)

MRI of the brain had been performed in a subset of deletion (n=65) and duplication (n=50) carriers, and showed mostly mild, non-recurrent

or normal findings (table S11 and S12). In deletion carriers the most frequent findings were enlarged ventricles 15.4% (10/65) and white

matter anomalies 13.8% (9/65) (table S11). In duplication carriers, cortical malformation/gyral simplifications are the most frequent finding

6.0% (3/50) (table S12). A normal MRI scan is reported in 36.9 % (24/65) of deletion carriers (table S11), and in 58% (29/50) of

duplication carriers (table S12).

S1.3. Major Malformation

The frequency of major malformations was similar in deletion 19.6% (64/326) and duplication 17.0% (30/176) carrying probands (p=0.55).

Among the 64 deletion probands who had a malformation, 39 had a single, and 25 had two or more malformations. For the 30 reciprocal

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. duplication probands, 22 presented one, and 8 two or more malformations. 4.6% (3/65) of deletion, and 5.3% (2/38) of duplication carrier

relatives presented an isolated malformation.

S1.4. Major Medical Conditions

The most common major medical conditions observed at similar frequencies in both deletion and duplication carriers are reduced hearing

4.1%, (16/391) and 5.1%, (11/214), respectively, and spine deformities 4.6% (18/391) and 4.2% (9/214), respectively (table S14 and S15).

S1.5. Dysmorphism

No recognizable phenotype has been linked to the 15q11.2 BP1-BP2 CNVs, and significant heterogeneity is usually reported in the

literature.3-5 37 38 The most frequently reported dysmorphic features in deletion carriers (n=391) in the clinically referred group are

hypertelorism (6.5%, n=22), microcephaly (6.2%, n=21) and high palate (5.0%, n=17). At least one dysmorphic feature was observed at

similar frequencies in deletion 33% (129/391) and duplication 33.2% (71/214) carriers. The great variability in dysmorphic features

together with similar frequencies in deletion and duplication carriers supports the absence of a dysmorphic phenotype in deletion carriers.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Supplementary Figures Figure S1. Distribution of CNVs based on pLI score and classification in the SJCHU database

Benign VOUS Pathogenic Counts 0 50 100 150 200

pLI_0.5_1 pLI_1_2 pLI_2_3

pLI group

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al.

Stacked Bar plot of the frequencies of 406 copy-number variants (CNVs) classified as pathogenic, unknown (VOUS) or benign according to their probability to be loss of function intolerant (pLI) score between 0.5 and 1.0 (pLI_0.5_1), 1.0 and 2.0 (pLI_1_2), or 2.0 and 3.0 (pLI_2_3). VOUS, variants of unknown significance; n, number of cases

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Figure S2. Estimation of the probability to be de novo in function of the pLI score of a CNV

Logistic regression of the probability to be de novo according to the probability to be loss of function intolerant (pLI) score of the copy- number variant (CNV) estimated for 2893 deletions with available transmission information adapted from Huguet and colleagues (2018)30 (supplementary materials and methods 1.6). The full blue line is the logistic regression and the dotted lines the 95% confidence intervals. The transmission mode is either 0=inherited or 1=de novo. n, number of cases.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. The mean number of genes are similar in deletion (25.4) and duplication (23.4) carrying probands, Student’s t-test p= 0.80. The median size of the additional pathogenic CNVs between deletion (2392,6 Kb) and duplication carrying probands (1355,5 Kb) is also similar, Wilcoxon Rank Sum test, p=1.0). The mean pLI score is further similar in deletion (5.7) and duplication (6.1) carrying probands, student’s t-test p=0.8635. We excluded proband carriers of sex chromosome aneuploidies from these analysis. CNV, copy number variation; kb, kilobase; n, number; Del, deletion; Dup, duplication.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Supplementary Tables

Table S1. Characteristics of published 15q11.2 deletion studies investigating neurodevelopmental disorders and congenital heart disease Cases Controls OR References Del, Total, Frequency Del, Total, Frequenc P-value Phenotype (95% CI) n n (%) n n y (%) Stefansson 2.73 26 4718 0.55 79 41194 0.19 6.0e-04 SZ/RP et al. 200839 (1.5-4.9) Mefford et 6.6 ID un- 8 1010 0.79 3 2493 0.12 3.0e-03 al. 200940 (1.8-5.0) explained Kirov et al. 1.9 30 3862 0.78 25 5973 0.42 2.6e-02 SZ 200941 (1.1-3.2) Dornboos et ∞ 9 1576 0.57 0 350 0.0 3.2e-01 ID/MCA al. 20095 (0.4-∞) Mefford et 6.1 5 517 0.96 4 2493 0.16 1.0e-02 IGE al. 201042 (1.3-0.7) De Kovel et 4.9 12 1234 0.97 6 3022 0.20 4.2e-04 IGE al. 201043 (1.8-3.2) DD/ASD/ Burnside et 1.6 69 17000 0.41 16 6329 0.25 8.7e-02 ADD/ al. 20113 (0.9-2.8) ADHD Cooper et al. 2.6 DD/ID/ 94 15767 0.60 19 8329 0.23 2.1e-05 201144* (1.6-4.3) CA Jiang et al. ∞ 3 198 1.5 0 198 0.0 2.5e-01 CAE 201145 (0.4-∞) DD/DF/ Sahoo et al. 10.0 96 13670 0.70 4 5674 0.07 1.45e-10 autism/ 201146* (3.8-7.5) seizures Rosenfeld et 2.2 DD/ID/ 203 25113 0.81 84 22246 0.38 <1.0e-04 al. 201247* (1.7-2.8) ASD Girirajan et 2.2 DD+/- 166 32587 0.51 19 8329 0.23 2.0e-04 al. 201248* (1.4-3.8) MCA

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Soemedi et 8.2 12 2256 0.53 1 1538 0.07 2.0e-03 CHD al. 201249 (1.1-63) De Wolf et 1.47 7 636 1.1 12 1603 0.75 4.2e-01 ASD al. 201350 (0.6-3.7) De Wolf et 1.79 ASD 6 448 1.3 12 1603 0.75 2.5e-01 al. 201350 (0.7-4.8) without ID Mullen et al. 5.0 IGE 5 359 1.4 54 18267 0.2 5.5e-03 201351 (1.5-12) without ID Mullen et al. 5.7 IGE with 1 60 1.5 54 18267 0.2 1.6e-01 201351 (0.1-4.4) ID Cafferkey et 2.2 ID/DD/ 83 14605 0.57 169 66462 0.25 <1.0e-04 al. 20144*** (1.7-2.9) DF/MCA Chaste et al. 1.18 ASD 8 2525 0.32 19 7086 0.27 6.6e-01 201452§ (0.4-2.8) (SSC) Kirov et al. 2.15 116 19547 0.59 227 81802 0.28 2.5e-10 SZ 201453** (1.7-2.7) Rees et al. 1.56 44 6882 0.64 26 6316 0.41 4.6e-02 SZ 201454* (0.9-2.5) Coe et al. 5.0 ID/DD/ 200 29085 0.69 27 19584 0.14 3.2e-21 201455* (3.5-7.0) MCA Rudd et al. ∞ 3 166 1.8 0 52 0.0 1.0 SZ 201417 (0.1-∞) Glessner et 12.1 2 538 0.37 0 1301 0.0 8.0e-02 CHD al. 201456 (0.6-252) Geng et al. 3.9 4 502 0.79 19 9170 0.21 3.0e-02 CHD 2014§§57 (1.3-11) Marshall et 1.8 98 21094 0.46 50 20227 0.25 1.3e-03 SZ al. 201758§§§ (1.2-2.6) In our meta-analyses we included the studies highlighted in bold. P values, Odds ratios, and confidence intervals are presented as reported by the authors or calculated using Fisher’s exact test. Frequencies of deletions in patients and controls were calculated for all studies.

*Includes cases from the same laboratory,** Includes cases from Kirov et al 2009, ***Control population includes cases from the following studies in the table: Rosenfeld et al. 2012; Cooper et al. 2011; de Kovel et al. 2010; Stefansson et al. 2008.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. §Controls are parents and siblings, §§Control cases from Soemedi et al., 2012 and Cooper et al., 2011, §§§Includes several schizophrenia datasets detailed in the paper.

Del, deletion; n, number of cases; OR, odds ratio; CI, confidence interval; SZ, schizophrenia; RP, related psychosis; CAE, childhood absence epilepsy; DD, developmental delay; ID, intellectual disability; ASD, autism spectrum disorder; ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; DF, dysmorphic features; CA, congenital anomalies; CMA, congenital multiple anomalies; IGE, idiopathic generalized epilepsy; IQ, intelligence quotient; SSC, Simons Simplex Collection.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Table S2. Characteristics of published 15q11.2 duplication studies investigating neurodevelopmental disorders Cases Controls OR References Dup, Total, Frequency Dup, Total, Frequenc P-value Phenotype (95% CI) n n (%) n n y (%) Van der 2.2 Zwaag et al. 8 849 0.9 4 945 0.42 2.5e-01 ASD (0.6-0.2) 201018 DD/ASD Burnside et 3.6 77 17000 0.45 8 6329 0.13 7.5e-05 /ADD/ al. 20113 (1.7-8.6) ADHD Cooper et al. 0.93 DD/ID/C 63 15767 0.40 36 8329 0.43 0.75 201144* (0.6-1.4) A DD/DF/ Sahoo et al. ∞ 83 13670 0.61 0 5674 0.0 4.2e-13 autism/ 201146* (9.2-∞) seizures Chaste et al. 1.5 ASD 20 2525 0.79 38 7086 0.54 1.7e-01 201452** (0.8-2.6) (SSC) Coe et al. 1.43 ID/DD/ 128 29085 0.44 60 19584 0.31 1.12e-02 201455* (1.0-1.9) MCA Reinthaler et 4.1 6 281 2.1 8 1512 0.53 1.4e-02§ IGE al. 201459 (1.2-3.6) In our meta-analyses we included the studies highlighted in bold. P-values, Odds ratios, and confidence intervals are presented as reported by the authors or calculated using Fisher’s exact test. Frequencies of duplications in patients and controls were calculated for all studies.

*Includes cases from the same laboratory, ** Controls are parents and siblings, §Uncorrected p-value (corrected p-value 0.17)

Dup, duplication; n, number of cases; OR, odds ratio; CI, confidence interval; DD, developmental delay; ID, intellectual disability; ASD, autism spectrum disorder; ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; DF, dysmorphic features; CA, congenital anomalies; CMA, congenital multiple anomalies; IGE, idiopathic generalized epilepsy; SSC, Simons Simplex Collection.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Table S3. Cognitive and behavioral results for 15q11.2 CNV carriers from the clinically referred group Deletion Duplication Carrier group/ Probands Relatives Probands Relatives Diagnosis (n=326) (n=65) (n=176) (n=38) ASD only, %(n) 12.9 (42) 3.1 (2) 13.6 (24) 5.3 (2)

ASD+DSM-V, 5.2 (17) 1.5 (1) 4.5 (8) -

% (n)

ID§, % (n) 42.3 (138) 23.1(15) 35.2 (62) 15.8 (6)

FSIQ, Mean ±SD, 70.9 ± 15.3 - 75.3 ± 23.0 -

(n with FSIQ) (20) (12)

NVIQ Mean ±SD, 75.5 ± 20.2 - 80.8 ± 15.0 -

(n with NVIQ) (13) (5)

VIQ Mean ±SD, 81.4 ± 16.5 - 88.5 ± 19.7 -

(n with VIQ) (12) (4)

Frequencies are based on results from cognitive tests or as reported by the referring clinicians (§ID) FSIQ, NVIQ or VIQ were not available for deletion or duplication carrier relatives.

DSM-V diagnoses included: attention-deficit/hyperactivity disorders, specific learning disorders, schizophrenia spectrum and other psychotic disorders, obsessive-compulsive and related disorders, sleep-wake disorders, and other conditions that may be a focus of clinical attention (abuse, neglect, maltreatment). §ID severity reported in deletion probands (35 mild, 23 moderate, 4 severe, 1 profound, 75 unspecified), and in their carrier relatives respectively (3 mild, 2 moderate, 10 unspecified).

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. §ID severity reported in duplication probands (22 mild, 7 moderate, 5 severe, 28 unspecified) and in their carrier relatives respectively (6 unspecified).

ASD, autism spectrum disorders; DSM-V, Diagnostic and Statistical Manual of Mental Disorders, 5th edition; CNV, copy number variant; ID, intellectual disability; n, number of cases; IQ, intelligence quotient; FSIQ, full scale IQ; NVIQ, non-verbal IQ; VIQ, verbal IQ; SD, standard deviation.

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Table S4. Comparing frequencies of additional pathogenic CNVs in 15q11.2 deletion and duplication carriers from the clinically referred group CNV No of Cases Frequency No (%) P-value (Del vs. Dup) Deletion probands+NDD 266 21(7.9) 0.85 Duplication probands+NDD 139 10 (7.2) Deletion probands-NDD 60 6 (10) 1.0 Duplication probands-NDD 37 3 (8.1) Deletion relative carriers 65 4 (6.2) 0.46 Duplication relative carriers 38 4 (10.5) All carriers are only reported once in the table, however 2 duplication probands carry two additional pathogenic CNVs and 1duplication proband carry three. Fisher’s exact test was used to assess the difference in frequency in each group.

CNV, copy number variant; +NDD, probands ascertained for neurodevelopmental disorders; -NDD, probands not ascertained for NDD; No, number; vs, versus

Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet

Jønch et al. Table S5. Characteristics of additional pathogenic CNVs detected in 15q11.2 deletion and duplication probands from the clinically referred group Additional Pathogenic CNV 15q11.2 CNV proband Boundaries (Hg19) No. of Chr Del/Dup Inheritance Size (kb) Gene symbols ID Del/Dup Inheritance Proximal Distal genes ACAP2, ADIPOQ, AHSG, APOD, ATP13A3, ATP13A4, ATP13A5, BCL6, CCDC50, CLDN1, CLDN16, CPN2, CRYGS, DGKG, DNAJB11, EIF4A2, ETV5, FAM43A, FETUB, FGF12, GMNC, GP5, HES1, HRASLS, HRG, IGF2BP2, IL1RAP, KNG1, LIPH, LPP, 1071 Del Mat 3 185036037 195748056 Del De novo 10,712,020 60 LRRC15, LSG1, MAP3K13, MASP1, MB21D2, MUC20, MUC4, OPA1, OSTN, P3H2, PPP1R2, PYDC2, RFC4, RPL39L, RTP1, RTP2, RTP4, SENP2, SST, ST6GAL1, TBCCD1, TMEM207, TMEM41A, TMEM44, TNK2, TP63, TPRG1, TRA2B, UTS2B, 29

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Jønch et al. XXYLT1 Atypical 22q11.2 AIFM3, CRKL, LRRC74B, LZTR1, 1090 Del Pat 22 21075575 21440514 Del Mat 364,940 10 P2RX6, PI4KA, SERPIND1, SLC7A4, SNAP29, THAP7

1660 Del Pat 15 31982510 32444044 Dup Pat 461,535 2 OTUD7A, CHRNA7

1671 Del Mat 2 211739676 213716573 Del Pat 1,976,898 1 ERBB4 AKAP17A, AMELY, ASMT, ASMTL, CD99, CRLF2, CSF2RA, DHRSX, GTPBP6, IL3RA, 1675 Del Mat Y 10761 8717986 Dup Unknown 8,707,226 23 P2RY8, PCDH11Y, PLCXD1, PPP2R3B, RPS4Y1, SHOX, SLC25A6, SRY, TBL1Y, TGIF2LY, TSPY2, ZBED1, ZFY ACKR3, AGAP1, AGXT, ANKMY1, ANO7, AQP12A, AQP12B, ASB1, ASB18, ATG4B, BOK, C2orf54, 1677 Dup Mat 2 236789722 243007359 Del De novo 6,217,638 61 CAPN10, COL6A3, COPS8, COPS9, CROCC2, D2HGDH, DTYMK, DUSP28, ERFE, ESPNL, FARP2, GAL3ST2,

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Jønch et al. GBX2, GPC1, GPR35, HDAC4, HDLBP, HES6, ILKAP, ING5, IQCA1, KIF1A, KLHL30, LRRFIP1, MLPH, MTERF4, NDUFA10, NEU4, OR6B2, OR6B3, OTOS, PASK, PDCD1, PER2, PPP1R7, PRLH, RAB17, RAMP1, RBM44, RNPEPL1, RTP5, SCLY, SEPT2, SNED1, STK25, THAP4, TRAF3IP1, TWIST2, UBE2F ARSD, ARSE, ARSF, ARSH, CD99, 1680 Dup Mat X 2143084 4674187 Del De novo 2,531,104 11 DHRSX, GYG2, MXRA5, PRKX, XG, ZBED1 ATP2A1, ATXN2L, CD19, LAT, 1693 Del Unknown 16 28824794 29042118 Del Unknown 217,325 9 NFATC2IP, RABEP2, SH2B1, SPNS1, TUFM AIFM3, ARVCF, C22orf39, CCDC188, CDC45, CLDN5, 1695 Del Mat 22 18894635 21505558 Dup Pat 2,610,924 46 CLTCL1, COMT, CRKL, DGCR14, DGCR2, DGCR6,

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Jønch et al. DGCR6L, DGCR8, GNB1L, GP1BB, GSC2, HIRA, KLHL22, LRRC74B, LZTR1, MED15, MRPL40, P2RX6, PI4KA, PRODH, RANBP1, RIMBP3, RTL10, RTN4R, SCARF2, SEPT5, SERPIND1, SLC25A1, SLC7A4, SNAP29, TANGO2, TBX1, THAP7, TMEM191B, TRMT2A, TSSK2, TXNRD2, UFD1, ZDHHC8, ZNF74 1697 Del Mat 2 50892647 51447014 Del Mat 554,368 1 NRXN1 ARL10, B4GALT7, CDHR2, CLTB, CPLX2, DBN1, DDX41, DOK3, DRD1, EIF4E1B, F12, FAF2, FAM153B, 1746 Dup Unknown 5 174843714 177107778 Dup Mat 2,264,065 42 FAM193B, FGFR4, GPRIN1, GRK6, HIGD2A, HK3, HRH2, KIAA1191, LMAN2, MXD3, NOP16, NSD1, PDLIM7, PFN3, PRELID1, PRR7,

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Jønch et al. RAB24, RGS14, RNF44, SFXN1, SIMC1, SLC34A1, SNCB, THOC3, TMED9, TSPAN17, UIMC1, UNC5A, ZNF346 ACP6, BCL9, CHD1L, FMO5, GJA5, GJA8, 1762 Dup Mat 1 145986956 147909235 Del Mat 1,922,280 13 GPR89B, NBPF10, NBPF11, NBPF12, NBPF19, NBPF20, PRKAB2 PLCXD1, GTPBP6, 1820 Del Mat X 93118 849078 Del Pat 755,961 4 PPP2R3B, SHOX ALDOA, ASPHD1, C16orf54, C16orf92, CDIPT, DOC2A, FAM57B, HIRIP3, INO80E, KCTD13, KIF22, MAZ, MVP, 1822 Del Unknown 16 29581457 30106101 Dup Unknown 524,645 24 PAGR1, PPP4C, PRRT2, QPRT, SEZ6L2, SPN, TAOK2, TBX6, TMEM219, YPEL3, ZG16 ASPN, AUH, BARX1, BICD2, C9orf129, CARD19, 1887 Del Unknown 9 94025532 97287508 Dup De novo 3,261,977 29 CENPP, ECM2, FAM120A, FAM120AOS, FGD3,

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Jønch et al. IARS, IPPK, MFSD14B, NFIL3, NINJ1, NOL8, NUTM2F, OGN, OMD, PHF2, PRSS47, PTPDC1, ROR2, SPTLC1, SUSD3, WNK2, ZNF169, ZNF484 ABCD1, ARHGAP4, ATP2B3, ATP6AP1, AVPR2, BCAP31, BGN, BRCC3, CETN2, CLIC2, CMC4, CSAG1, CSAG3, CTAG1A, CTAG1B, CTAG2, DKC1, DNASE1L1, DUSP9, EMD, F8, F8A1, F8A2, F8A3, FAM3A, FAM50A, 1889 Del Unknown X 151903976 155170042 Dup Unknown 3,266,067 84 FAM58A, FLNA, FUNDC2, G6PD, GAB3, GDI1, H2AFB1, H2AFB2, H2AFB3, HAUS7, HCFC1, IDH3G, IKBKG, IRAK1, L1CAM, LAGE3, MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MECP2, MPP1, MTCP1, NAA10, NSDHL,

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Jønch et al. OPN1LW, OPN1MW, OPN1MW2, OPN1MW3, PDZD4, PLXNA3, PLXNB3, PNCK, PNMA3, PNMA5, PNMA6A, PNMA6E, RAB39B, RENBP, RPL10, SLC10A3, SLC6A8, SMIM9, SPRY3, SRPK3, SSR4, TAZ, TEX28, TKTL1, TMEM187, TMLHE, TREX2, UBL4A, VAMP7, VBP1, ZFP92, ZNF185, ZNF275 ACSL1, ADAM29, AGA, ANKRD37, ASB5, C4orf47, CASP3, CCDC110, CDKN2AIP, CENPU, CEP44, CFAP97, CLDN22, CLDN24, CYP4V2, DCTD, 1890 Del Unknown 4 172602773 187209940 Del Unknown 14,607,168 51 ENPP6, F11, FAM149A, FBXO8, GALNT7, GALNTL6, GLRA3, GPM6A, HAND2, HELT, HMGB2, HPGD, ING2, IRF2, KLKB1, LRP2BP, NEIL3, PDLIM3, PRIMPOL,

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Jønch et al. RWDD4, SAP30, SCRG1, SLC25A4, SNX25, SORBS2, SPATA4, SPCS3, STOX2, TENM3, TLR3, TRAPPC11, UFSP2, VEGFC, WDR17, WWC2 BTG3, C21orf91, CHODL, CXADR, HSPA13, LIPI, LOC388813, 1893 Del Unknown 21 14546389 22849097 Del De novo 8,302,709 14 NCAM2, NRIP1, POTED, RBM11, SAMSN1, TMPRSS15, USP25 ANKRD34A, ANKRD35, CD160, GPR89A, HFE2, ITGA10, LIX1L, NBPF10, NBPF11, NBPF19, NBPF20, 1902 Del Unknown 1 145031367 146201635 Dup Mat 1,170,269 24 NBPF9, NOTCH2NL, NUDT17, PDE4DIP, PDZK1, PEX11B, PIAS3, POLR3C, POLR3GL, RBM8A, RNF115, SEC22B, TXNIP 1958 Del Unknown 2 50725729 50811226 Del Unknown 85,498 1 NRXN1 2067 Dup Unknown X 60001 58313676 Del De novo 58,253,676 333 2067 Dup Unknown X 61728817 155260560 Dup Unknown 93,531,744 508 ADRA2B, 2067 Dup Unknown 2 96734645 98118200 Dup Unknown 1,383,556 22 ANKRD23,

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Jønch et al. ANKRD36, ANKRD39, ARID5A, ASTL, CIAO1, CNNM3, CNNM4, DUSP2, FAHD2B, FAM178B, FER1L5, ITPRIPL1, KANSL3, LMAN2L, NCAPH, NEURL3, SEMA4C, SNRNP200, STARD7, TMEM127 ACAD8, B3GAT1, GLB1L2, GLB1L3, IGSF9B, JAM3, 2072 Del Pat 11 132058695 134816461 Del Mat 2,757,767 12 NCAPD3, NTM, OPCML, SPATA19, THYN1, VPS26B 4018 Del Pat 2 148740842 148829378 Del De novo 88,537 2 MBD5, ORC4 BTAF1, CEP55, CPEB3, CYP26A1, CYP26C1, EXOC6, FFAR4, FGFBP3, 4024 Del Mat 10 93660359 96058433 Del De novo 2,398,075 19 FRA10AC1, HHEX, IDE, KIF11, LGI1, MARCH5, MYOF, PDE6C, PLCE1, RBP4, SLC35G1 82133 Del Pat X 296520 155228049 Dup Unknown 154,931,530 839 AIFM3, ARVCF, C22orf29, C22orf39, CDC45, CLDN5, 82139 Del Unknown 22 18919528 21460595 Dup Unknown 2,541,068 45 CLTCL1, COMT, CRKL, DGCR14, DGCR2, DGCR6L,

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Jønch et al. DGCR8, GNB1L, GP1BB, GSC2, HIRA, KLHL22, LOC388849, LRRC74B, LZTR1, MED15, MRPL40, P2RX6, PI4KA, PRODH, RANBP1, RIMBP3, RTN4R, SCARF2, SEPT5, SERPIND1, SLC25A1, SLC7A4, SNAP29, TANGO2, TBX1, THAP7, TMEM191B, TRMT2A, TSSK2, TXNRD2, UFD1L, ZDHHC8, ZNF74 ADGRV1, ARRDC3, ARSK, C5orf30, CAST, CETN3, CHD1, EFNA5, ELL2, ERAP1, ERAP2, FAM172A, FAM174A, FAM81B, FBXL17, GIN1, 82190 Del Unknown 5 86764781 107688118 Del Unknown 20,923,338 43 GLRX, GPR150, KIAA0825, LIX1, LNPEP, LYSMD3, MBLAC2, MCTP1, MEF2C, NR2F1, NUDT12, PAM, PCSK1, POLR3G, POU5F2, PPIP5K2,

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Jønch et al. RFESD, RGMB, RHOBTB3, RIOK2, SLCO4C1, SLCO6A1, SLF1, SPATA9, ST8SIA4, TMEM161B, TTC37 ALDOA, ASPHD1, C16orf54, C16orf92, CDIPT, DOC2A, FAM57B, GDPD3, HIRIP3, INO80E, KCTD13, KIF22, 82194 Del Unknown 16 29657192 30188269 Del Unknown 531,078 26 MAPK3, MAZ, MVP, PAGR1, PPP4C, PRRT2, QPRT, SEZ6L2, SPN, TAOK2, TBX6, TMEM219, YPEL3, ZG16 ACTN2, ADSS, AHCTF1, AKT3, BECN2, C1orf100, C1orf101, C1orf229, CEP170, CHML, CHRM3, CNST, COX20, DESI2, 82237 Del Unknown 1 236679343 249208105 Dup De novo 12,528,763 92 EFCAB2, EXO1, FH, FMN2, GCSAML, GREM2, HEATR1, HNRNPU, KIF26B, KMO, LGALS8, LYPD8, MAP1LC3C, MT1HL1, MTR, NLRP3, OPN3,

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Jønch et al. OR11L1, OR13G1, OR14A16, OR14C36, OR14I1, OR1C1, OR2AK2, OR2B11, OR2C3, OR2G2, OR2G3, OR2G6, OR2L13, OR2L2, OR2L3, OR2L5, OR2L8, OR2M2, OR2M3, OR2M4, OR2M5, OR2M7, OR2T1, OR2T10, OR2T11, OR2T12, OR2T2, OR2T27, OR2T29, OR2T3, OR2T33, OR2T34, OR2T35, OR2T4, OR2T5, OR2T6, OR2T8, OR2W3, OR2W5, OR6F1, PGBD2, PLD5, RGS7, RYR2, SCCPDH, SDCCAG8, SH3BP5L, SMYD3, TFB2M, TRIM58, VN1R5, WDR64, ZBTB18, ZNF124, ZNF496, ZNF669, ZNF670, ZNF672, ZNF692, ZNF695, ZP4 BLK, C8orf74, CTSB, 82244 Del Pat 8 9465882 11858466 Del De novo 2,392,585 19 DEFB134, DEFB135,

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Jønch et al. DEFB136, FAM167A, FDFT1, GATA4, MSRA, MTMR9, NEIL2, PINX1, PRSS55, RP1L1, SLC35G5, SOX7, TNKS, XKR6 ANKRD11, 82258 Dup Unknown 16 89327977 89459292 Del Unknown 131,316 2 LOC100287036 AIFM3, ARVCF, C22orf29, C22orf39, CDC45, CLDN5, CLTCL1, COMT, CRKL, DGCR14, DGCR2, DGCR6L, DGCR8, GNB1L, GP1BB, GSC2, HIRA, KLHL22, LOC388849, LRRC74B, LZTR1, MED15, MRPL40, 82284 Dup Unknown 22 18919528 21460595 Del Unknown 2,541,068 45 P2RX6, PI4KA, PRODH, RANBP1, RIMBP3, RTN4R, SCARF2, SEPT5, SERPIND1, SLC25A1, SLC7A4, SNAP29, TANGO2, TBX1, THAP7, TMEM191B, TRMT2A, TSSK2, TXNRD2, UFD1L, ZDHHC8, ZNF74 82302 Dup Unknown X 18492669 18541331 Del Unknown 48,663 1 CDKL5 (male)

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Jønch et al. ARVCF, C22orf29, C22orf39, CDC45, CLDN5, CLTCL1, COMT, DGCR14, DGCR2, DGCR8, GNB1L, GP1BB, GSC2, HIRA, 82305 Dup Pat 22 18919528 20246877 Dup Pat 1,327,350 28 LOC388849, MRPL40, PRODH, RANBP1, RTN4R, SEPT5, SLC25A1, TANGO2, TBX1, TRMT2A, TSSK2, TXNRD2, UFD1L, ZDHHC8 AIFM3, CRKL, KLHL22, LRRC74B, LZTR1, MED15, 82305 Dup Pat 22 20734765 21460595 Dup Mat 725,831 14 P2RX6, PI4KA, SCARF2, SERPIND1, SLC7A4, SNAP29, THAP7, ZNF74 82321 Dup Pat 5 151252195 151547866 Del Pat 295,672 1 GLRA1 BCL2L13, BID, 82351 Dup Unknown 22 18116245 18641290 Del Mat 525,046 6 MICAL3, PEX26, TUBA8, USP18 CRLF2, CSF2RA, 82354 Dup Unknown X 229552 1480494 Del Mat 1,250,943 6 GTPBP6, IL3RA, PPP2R3B, SHOX ADAMTSL3, ALPK3, AP3B2, 82363 Del Mat 15 83215606 85683858 Del De novo 2,468,253 23 BNC1, BTBD1, C15orf40, CPEB1, FAM103A1, FSD2,

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Jønch et al. GOLGA6L4, HDGFRP3, HOMER2, NMB, PDE8A, SEC11A, SH3GL3, SLC28A1, TM6SF1, UBE2Q2L, WDR73, WHAMM, ZNF592, ZSCAN2 ADM2, ALG12, ARSA, CHKB, CPT1B, CRELD2, DENND6B, HDAC10, IL17REL, KLHDC7B, LMF2, MAPK11, MAPK12, MAPK8IP2, MIOX, 82375 Del Unknown 22 50283439 51175792 Del Unknown 892,354 32 MLC1, MOV10L1, NCAPH2, ODF3B, PANX2, PIM3, PLXNB2, PPP6R2, SBF1, SCO2, SELENOO, SHANK3, SYCE3, TRABD, TTLL8, TUBGCP6, TYMP 82380 Dup Unknown X 2744701 154929280 Dup Unknown 152,184,580 822 AMELY, CD24, CDY2A, CDY2B, DDX3Y, EIF1AY, HSFY1, HSFY2, 82380 Dup Unknown Y 2654967 24396348 Del Unknown 21,741,382 39 KDM5D, NLGN4Y, PCDH11Y, PRORY, PRY, PRY2, RBMY1A1,

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Jønch et al. RBMY1B, RBMY1D, RBMY1E, RBMY1F, RBMY1J, RPS4Y1, RPS4Y2, SRY, TBL1Y, TGIF2LY, TMSB4Y, TSPY1, TSPY10, TSPY2, TSPY3, TSPY4, TSPY8, USP9Y, UTY, VCY, VCY1B, XKRY, XKRY2, ZFY ANNOVAR (http://annovar.openbioinformatics.org) was used for counting the number of genes. Del, deletion; Dup, duplication; Pat, paternal; Mat, maternal; Chr, chromosome; kb, kilobase; No, number

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Table S6. Additional genetic variants identified in 15q11.2 deletion and duplication probands from the clinically referred group 15q11.2 ID Additional variant Classification/phenotype Inheritance CNV Pathogenic, Karyotype 1066 Dup Trisomy 21 mosaicism Unknown 47,XX,+21[41]/46,XX[29] ~20% of cells SHANK3 c.3796G>A Non synonymous mutation 1068 Del (p.Ala1266Thr) in exon 21 unclassified variant Unknown CDMP1 c.1429C>G Unknown classification,

1088 Del (p.Leu477Val) in Acromesomelic Unknown exon 2 chondrodysplasias Karyotype Apparently balanced 1824 Del De novo 46,XX,t(2;13) (p24.2;q32?) translocation Pathogenic, 1851 Del PACS1 (c.607C>T –R203W) De novo PACS1 syndrome Karyotype Apparently balanced 1884 Del Maternal 46,XY,t(7;17)(q32.3;q25.1) translocation Karyotype 2017 Dup Double Y syndrome Unknown 47,XYY Pathogenic 2035 Del Low level mosaicism Iso(Xq) Mild or full Turner Unknown syndrome Karyotype Pathogenic 2037 Del Unknown 47,XXY Klinefelter syndrome Karyotype 2043 Del Likely benign Paternal Inv(13)(q22q34) Karyotype Apparently balanced 2047 Del De novo 46,XY,t(3;13)(q12;q22) translocation Pathogenic, SLC2A c.985G>A 4042 Dup Glut1 deficiency De novo (p.Glu329Lys) syndrome 82119 Del ENG c.360+1G>A Pathogenic, Unknown

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Jønch et al. (IVS3+1G>A) Mb. Osler

RASA1 c.1528G>T in exon 11 Pathogenic, Mother has 82155 Del introduce a stop codon CMAVM; MIM 608354 same phenotype (Glu510Term)

GABRG2 c.1088G>A Likely pathogenic variant, 82209 Del (p.Arg363Gln) heterozygous De novo Dravet syndrome mutation in exon 9 Karyotype 46,XY,der(3)(3q13.32-> 3q23::3q11.2 ::3q25.1-> 3q25.33::18q11.2-> Pathogenic, unbalanced, 18qter),der(3;18)(3pter-> 82229 Del not possible to establish De novo 3q11.1::18q11.1-> breakpoints by array 18q11.2::3q11.2-> 3q13.32::3q23-> 3q25.1::3q25.33-> 3q27::18p11.2-> 18pter) 47XY,+der(22),t(16;22) Maternal Pathogenic, 82282 Dup (p13.3;q12.3)mat.ish balanced Unbalanced translocation der(22)(tel16p+) t(16;22) SCN1B c.641G>A Variant of unknown 82300 Dup Unknown (p.Arg214Gln) significance CNV, copy number variant; Del, deletion; Dup, duplication; t, translocation

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Jønch et al. Table S7. Transmission and de novo frequency in previous published 15q11.2 deletion studies and case series Gender Inheritance No. of Parental Reference Not De Phenotypic Information cases Male Female Maternal Paternal origin Unknown specified Novo unknown DD/ID/speech Murthy et al. 1 1 1 impairment/neurologic 20079 al disorder Stefansson et 26 16 10 26 SZ/RP al. 200839 Doornbos et ID/DD (motor and 9 7 2 2 3 4 al. 20095 speech)/MCA/DF/BP Kirov et al. 30 30 30 SZ 200941 Mefford et al. 8 8 8 ID unexplained 200940 Mefford et al. Idiopathic generalized 5 5 2 1 2 201042 and focal epilepsies de Kovel et al. Idiopathic generalized 12 3 9 3 2 7 201043 epilepsy DD (motor and Burnside et al. speech)/ASD/ 69 44 25 1 20 48 20113 ADD/ADHD/NP and/or BP Cooper et al. 94 94 94 ID/DD/CA 201144 Sempere Perez Psychomotor 1 1 1 et al. 60 2011 retardation, DF Von der Lippe Learning difficulties/DD 7 5 2 1 5 1 et al. 14 2011 * and/or BP Jiang et al. Childhood absence 3 3 1 2 201245 epilepsy

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Jønch et al. Sahoo et al. 85 85 2 1 82 DD/DF/Autism/Seizures 201146 Abdelmoity et ID/ 16 9 7 4 3 2 7 al. 20122 DD/ASD/Epilepsy/DF Rosenfeld et DD/ID/ASD/MCA/Epile 203 203 27 176 al. 201247 psy/DF Girirajan et al. 166 166 1 10 4 151 DD/ID/+/-‐ CM 201248 Madrigal et al. ID/DD (motor and 2 1 1 2 20128 speech)/ASD/DF Soemedi et al. 12 7 5 12 CHD sporadic 201249 De Wolf et al. DD/ID/ASD/Epilepsy/ 39 24 15 1 13 10 15 201350 CA/NP and/or BP Jähn et al. 3 1 2 2 1 Pediatric epilepsies 20136 Epilepsy +/-‐ ID (childhood or early Mullen et al. 6 2 4 1 3 2 onset absence epilepsy 201351 or generalized tonic-‐ clonic seizures) Wong et al. Tracheoesophageal 2 2 2 201315 fistula, cataracts Kirov et al. 116 116 116 SZ 201453 Usrey et al. Congenital 2 1 1 1 1 201413 Arthrogyposis Geng et al. 3 3 3 CHD 201457 Glessner et al. 2 2 2 CHD 201456 Rudd et al. 3 1 2 2 1 SZ

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Jønch et al. 201417 Cognitive Jerkovich et al. 1 1 1 deficit/ADHD/speech 20147 delay/Cataract DD (motor and Cafferkey et al. 83 56 27 83 speech)/ASD/Epilepsy/ 20144 DF/BP Chaste et al. 8 8 1 3 4 ASD (SSC) 201452 Coe et al. ID/DD/MCA/CHD/ 200 200 200 201455** Epilepsy/ASD Rees et al. 44 44 44 SZ 201454 Hashemi et al. 35 6 6 23 5 16 11 3 DD/CA/NP/DF 201537 Tayeh et al. 1 1 1 DD/DF 201511 Vanlerberghe 52 31 21 6 15 13 18 DD/CHD/Epilepsy/BP et al. 38 2015 Periventricula nodular Radley et al. 1 1 1 heterotopia/ Learning 201561 difficulties/BP/DF Zhang et al. ASD with regression 2 2 2 201516 (Monozygotic twins) CHD syndromic Costain et al. (complete 1 1 1 201662 transposition of the great arteries) ASD/ID/ADD/Anxiety/ Picinelli et al. 1 1 1 OCD/Language delay/ 201610 Memory impairment Chen et al. 2 1 1 2 DD (motor and

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Jønch et al. 201763 speech)/NP and/or BP Marshall 98 98 98 SZ et al. 58 2017 § Ulfarsson et al. Dyslexia and 71 24 27 20 71 201764§§ Dyscalculia Total 1525 247 173 1105 21 83 68 50 1303 We only included previous clinical series and case-control studies specifically investigating the 15q11.2 deletion. General populations cohorts are not included in the table. We calculated the de novo frequency in all deletion literature cases=9.5% (21/222), 95% CI: (6.0-14.2). To establish the transmission in deletion carriers in the clinically referred group, without counting cases from the literature twice, we performed a simple subtraction of these cases that included 57 deletions (3 de novo and 54 parental transmissions) from the overall number before conducting the analysis. The resulting de novo rate of 15q11.2 deletion in the clinically referred group including deletion carriers from the literature 2-11 13-17 is=5.3% (8/151), 95% CI: (2.3-10.2).

*Include one sibling, **Include cases from Cooper et al. 2011, §Include previous schizophrenia studies and meta-analysis, §§Gender information includes a subset of 51 deletion carriers who had a structural MRI.

ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; ADD, attention deficit disorder; BP, behavioral problems; CA, congenital abnormalities; CHD, congenital heart disease; CM, congenital malformation; DD, developmental delay; DF, dysmorphic features; ID, intellectual disability; MCA, multiple congenital anomalies; NP, neurological problems; No, number; OCD obsessive compulsive disorder; RP, related psychosis; SSC, Simon Simplex Collection; SZ, schizophrenia.

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Jønch et al. Table S7B. Transmission and de novo frequency in previous published 15q11.2 duplication studies and case series Gender Inheritance No. of Parental Phenotypic Reference Not De cases Male Female Maternal Paternal origin Unknown Information specified Novo unknown van der Zwaag 3 1 2 2 1 ASD et al. 18 2010 * DD (motor and Burnside et al. speech)/ASD/ 77 54 23 1 2 3 17 54 20113 ADD/ADHD/NP and/or BP Cooper et al. 63 63 63 DD/ID/CA 201144 Sahoo et al. DD/DF/Autism/ 63 63 2 61 201146** Seizures Neuropsychiatric Abdelmoity et 10 6 3 1 10 disorders/ al. 20122 Dysmorphism Chaste et al. 20 20 9 11 ASD (SSC) 201452 Glessner et al. 2 2 2 CHD 201456 Coe et al. ID/DD/MCA/CHD/ 128 128 128 201455*** Epilepsy/ASD Tonni et al. 1 1 1 MCA 201512 ID/DD Picinelli et al. 5 4 1 3 1 1 (Motor and Speech) 201610 /ASD/ADHD/BP Benitez-‐ Cognitive/Language Burraco et al. 3 3 3 impairment 201765§

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Jønch et al. Ulfarsson et al. Dyslexia and 104 39 65 104 201764§§ Dyscalculia Total 478 107 94 277 3 16 21 18 420 We included previous clinical series and case-control studies specifically investigating the 15q11.2 duplication. General populations cohorts are not included in the table. We calculated the de novo frequency in all duplication literature cases=5.2% (3/58), 95% CI: (1.1-14.4). To establish the transmission in duplication carriers in the clinically referred group, without counting cases from the literature twice, we performed a simple subtraction of these cases that included 31 duplications (1 de novo and 30 parental transmissions) from the overall number before conducting the analysis. The resulting de novo frequency of the 15q11.2 duplication in the clinically referred group including duplication carriers from the literature2 3 10 12 18 is =1.9% (1/54), 95% CI: (0.0-9.9).

*3 family members carry the dup, one proband, **we removed general population cases from Itsara et al. 2009 66, why n=63, ***the study includes cases from Cooper et al. 2011, §3 twin children.

ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; ADD, attention deficit disorder; BP, behavioral problems; CA, congenital abnormalities; CHD, congenital heart disease; DD, developmental delay; DF, dysmorphic features; ID, intellectual disability; MCA, multiple congenital anomalies; NP, neurological problems; SSC, Simon Simplex Collection.

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Jønch et al. Table S8. Transmission and de novo frequency of the 15q11.2 CNVs in the DECIPHER database Deletion Duplication Inheritance/CNV (n=306) (n=123) De Novo 12 (3.9%) 6 (4.9%)* Inherited from normal parent 37 (12.1%) 36 (29.3%) Inherited from parent with similar phenotype as child 16 (5.2%) 5 (4.1%) Inherited from parent with unknown phenotype 4 (1.3%) 2 (1.6%) Maternally inherited, constitutive in mother 38 (12.4%) 19 (15.4%) Paternally inherited, constitutive in father 31 (10.1%) 10 (8.1%) Inheritance unknown 168 (54.9%) 45 (36.6%) *One case with a mosaic de novo duplication was not included We calculated the de novo frequency in the 15q11.2 deletion and duplication from the DECIPHER dataset at 8.7% (12/138, 95% CI: 4.6-14.7), and 7.7% (6/78, 95% CI: 2.9-16.0), respectively.

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Jønch et al. Table S9. Comparing frequencies of ASD in 15q11.2 deletion and duplication probands from the clinically referred group CNV Frequency %, No P-value (Del vs. Dup) All deletion probands 12.9 (42/326) 0.89 All duplication probands 13.6 (24/176) NDD-deletion probands 15.8 (42/266) 0.78 NDD-duplication probands 17.3 (24/139) Deletion probands* 12.4 (37/299) 0.66 Duplication probands* 14.1 (23/163) Deletion probands** 11.9 (35/292) 0.47 Duplication probands** 14.4 (23/160) *After removal of 27 deletion and 13 duplication probands with additional pathogenic CNVs. Among these cases 5 deletion and 1 duplication probands with an additional pathogenic CNV had a history of ASD. **After removal of further 7 deletion and 3 duplication probands with additional pathogenic SNVs or chromosomal rearrangements from probands with additional pathogenic CNVs. 2 deletion, but none of the duplication probands among these cases had a history of ASD.

ASD, autism spectrum disorder; CNV, copy number variant; No, number; Del, deletion; Dup, duplication; vs., versus; NDD, probands ascertained with neurodevelopmental disorders; SNVs, single nucleotide variants.

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Jønch et al. Table S10. Comparing frequencies of epilepsy in 15q11.2 CNV carriers from the clinically referred group CNV Frequency %, No P-value (Del vs. Dup) All deletion carriers 12.8 (50/391) 0.79 All duplication carriers 11.7 (25/214) Deletion probands 15.3 (50/326) 0.78 Duplication probands 14.2 (25/176) Deletion probands* 15.1 (45/299) 1.0 Duplication probands* 14.7 (24/163) Deletion probands** 15.1 (44/292) 0.89 Duplication probands** 14.4 (23/160) *After removal of 27 deletion and 13 duplication probands with additional pathogenic CNVs. Among these cases 5 deletion and 1duplication proband with an additional pathogenic CNV had a history of epilepsy. **After removal of further 7 deletion and 3 duplication probands with additional pathogenic SNVs or chromosomal rearrangements from probands with additional pathogenic CNVs. 1 deletion and 1duplication proband among these cases had a history of epilepsy.

CNV, copy number variant; No, numbers; Del, deletion; Dup, duplication; vs., versus; SNVs, single nucleotide variants

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Table S11. Neurological features in 15q11.2 deletion carriers from the clinically referred group according to ascertainment

Probands Relatives All carriers DELETION

Epilepsy Type +NDD -NDD n=65 n=391 (%) n=266 n=60 Unclassified 18 1 0 19 (4.9) Generalized 21 0 0 21 (5.4) Focal 8 1 0 9 (2.3) Infantile Spasms 1 0 0 1 (0.3) All seizure types 48 2 0 50 (12.8) Neurological symptoms Axial hypotonia 3 3 0 6 (1.5) Peripheral hypotonia 24 8 0 32 (8.2) Hyperreflexia 5 2 0 7 (1.8) Motor dyspraxia 12 0 1 13 (3.3) Verbal dyspraxia 6 0 0 6 (1.5) Motor clumsiness 4 1 1 6 (1.5) Coordination problems 13 0 0 13 (3.3) Gait disorder 3 0 0 3 (0.8) Ataxia 10 1 0 11 (2.8) Migraine 0 1 0 1 (0.3) Abnormal movements* 7 1 1 9 (2.3) Other** 28 4 2 34 (8.7)

MRI CNS n=55 n=8 n=2 n=65 Cortical malformation/gyral 4 2 0 6 (9.2) simplification Myelination delay 1 0 0 1 (1.5) White matter anomalies 8 1 0 9 (13.8)

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Jønch et al. Corpus callosum abnormality 5 2 0 7 (10.8) (hypoplasia/agenesis) Ventricular anomalies 7 3 0 10 (15.4) Posterior fossa abnormality (cerebellar 1 0 0 1 (1.5) hypoplasia) Migration disorders 1 0 0 1 (1.5) Hypophyseal anomalies 1 0 0 1 (1.5) Normal 23 0 1 24 (36.9) Other*** 11 3 1 15 (23.0) Carriers can have more than one neurological finding. Seizures syndromic classification includes: idiopathic generalized epilepsy (IGE) (n=16), West syndrome (n=1), Dravet syndrome (n=1), and unspecified seizures (n=32). Febrile seizures (n=3) are not shown in the table. IGE includes Childhood and Juvenile absence epilepsy, Juvenile myoclonic epilepsy and epilepsies with generalized tonic-clonic seizures.

*Abnormal movements includes: chorea (n=1), dyskinesia (n=1), tics (n=1), action tremor (n=2), rest tremor (n=1), unspecified (n=3) **Other neurological features includes: statokinetic cerebellar syndrome (n=3), cerebral palsy (n=1), muscular atrophy (n=3), spastic quadriparesis (n=1), asthenia/myopathy (n=4), balance problems (n=10), feet intoing gait (n=2), severe swallowing problems (n=1), limited shoulder abduction (n=1), disc herniation (n=2 relatives), congenital torticollis (n=2), unspecified motor problems (n=4). ***Other cerebral MRI findings includes: Dandy Walker variant, epidermal cyst, small angioma and small arachnoid cyst, unusually thick anterior commissure, enlarged (10 mm) cavum septum pellucidum, dilatation of the left fronto parietal sulci but normal gyration, corpus callosum moniliform (benign variant), unspecified MRI findings.

+NDD, probands ascertained for neurodevelopmental disorders; -NDD; probands not ascertained for NDDs; MRI, magnetic resonance imaging; CNS, central nervous system; SD, standard deviation; n, number of cases.

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Jønch et al. Table S12. Neurological features in 15q11.2 duplication carriers from the clinically referred group according to ascertainment

Probands Relatives All carriers DUPLICATION

Epilepsy Type +NDD -NDD n=38 n= 214 (%) n=139 n=37 Unclassified 7 0 0 7 (3.3) Generalized 10 0 0 10 (4.7) Focal 7 0 0 7 (3.3) Infantile Spasms 1 0 0 1 (0.5) All seizure Types 25 0 0 25 (11.7) Neurological symptoms Axial hypotonia 4 0 0 4 (1.9) Peripheral hypotonia 24 0 1 25 (11.7) Peripheral hypertonia 1 0 0 1 (0.5) Hyperreflexia 2 1 0 3 (1.4) Motor dyspraxia 3 0 0 3 (1.4) Verbal dyspraxia 2 0 0 2 (0.9) Motor clumsiness 3 0 0 3 (1.4) Coordination problems 10 0 0 10 (4.7) Gait disorder 1 0 0 1 (0.5) Ataxia 4 0 0 4 (1.9) Migraine 2 0 0 2 (0.9) Abnormal movements* 5 1 1 7 (3.3) Other** 20 3 1 24 (11.2)

MRI CNS n=39 n=6 n=5 n=50 Cortical malformation/gyral 3 0 0 3 (6.0) simplification Myelination delay 1 0 0 1 (2.0) White matter anomalies 1 0 1 2 (4.0)

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Jønch et al. Corpus callosum abnormality 1 1 0 2 (4.0) (hypoplasia/agenesis) Ventricular anomalies 0 1 0 1 (2.0) Migration disorders 1 0 0 1 (2.0) Normal 25 1 3 29 (58.0) Other*** 8 3 1 12 (24.0) Carriers can have more than one neurological finding. Seizures syndromic classification includes: idiopathic generalized epilepsy (IGE) (n=1), early-onset epileptic encephalpathy (n=2), epileptic encephalopathy with continous spike and wave during sleep (CSWS) (n=2), Lennox-Gastaut syndrome (n=1), and unspecified seizures (n=19). Febrile seizures (n=4) are not shown in the table.

*Abnormal movements includes: dystonia (n=2), tics (n=3), dyskinesia (n=1), action tremor (n=1), rest tremor (n=1), unspecified (n=2) **Other neurological features includes: paroxymal abnormal position of fingers and toes (n=1), myopathy (n=6), spastic diplegia/quadriparesis (n=3), restless leg syndrome (n=1), benign familial joint hypermobility syndrome (n=1), short Achilles tendons (n=1), tight right food adductor (n=1), balance problems (n=3), congenital torticollis (n=2), disc herniation (n=1 relative), unspecified motor problems (n=4). ***Other cerebral MRI findings includes: MRI findings suggestive of perivenous encephalitis, bilateral encephalomalacia of occipital lobes, molar tooth sign, acquired cerebellar atrophy, unspecified MRI findings.

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Jønch et al. Table S13. Comparing frequencies of congenital heart disease in 15q11.2 CNV carriers from the clinically referred group CNV Frequency %, No P-value (Del vs. Dup) All deletion carriers 7.7% (30/391) 0.17 All duplication carriers 4.7% (10/214) Deletion probands 8.9% (29/326) 0.22 Duplication probands 5.7% (10/176) Deletion probands* 9.0% (27/299) 0.37 Duplication probands* 6.1% (10/163) Deletion probands** 8.9 (26/292) 0.27 Duplication probands** 5.6 (9/160) *After removal of 27 deletion and 13 duplication probands with additional pathogenic CNVs. Among these cases 2 deletion and none of the duplication probands with an additional pathogenic CNV had a history of congenital heart disease. **After removal of further 7 deletion and 3 duplication probands with additional pathogenic SNVs or chromosomal rearrangements from probands with additional pathogenic CNVs. 1 deletion and 1duplication proband among these cases had a history of congenital heart disease.

CNV, copy number variant; No, number of cases; Del, deletion; Dup, duplication; vs., versus; SNVs, single nucleotide variants.

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Jønch et al. Table S14. Malformation and medical conditions in 15q11.2 deletion carriers from the clinically referred group according to ascertainment

Probands Relatives All carriers DELETION

Congenital malformation +NDD -NDD n=65 n=391 (%) n=266 n=60 Coloboma/cataract/ microphthalmia/eccentric Ophthalmic pupils with 6 5 0 11 (2.8) proptosis/enotropion/ chorioretinal lesions Cleft +/- lip palate, submucous cleft, bifid Orofacial 6 4 1 11 (2.8) uvula, Pierre Robin sequence Craniosynostosis, Craniofacial metopic ridges, 3 2 0 5 (1.3) trigonocephaly Vertebral anomalies, rib Osteo- anomalies, other osseous 2 5 0 7 (1.8) articular anomalies* Cardio- Structural heart defect** 11 18 1 30 (7.7) vascular Cardiomyopathy 0 2 0 2 (0.5) Omphalocele, duodenal web, trachea-esophagal fistula, esophageal Digestive 1 3 0 4 (1.0) atresia, anteriorly displaced anus, imperforate anus Vesico-ureteric reflux, Urinary tract hydronephrosis, duplex 1 2 1 4 (1.0) kidney Genitalia Cryptorchidism, ectopic 11 4 0 15 (3.8)

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Jønch et al. testis, hypospadia, phimosis, hydrocele, gonadal dysgenesis, clitoris hypertrophy Total 41 45 3 89 (22.8) Medical conditions Reduced vision 3 0 0 3 (0.8) Other eye conditions§ 3 2 1 6 (1.5) Hearing impairment/deafness 12 3 1 16 (4.1) Scoliosis/kyphosis/lordosis/torticollis 16 1 1 18 (4.6) Recurrent infections 1 0 1 2 (0.5) Tumors§§ 0 3 0 3 (0.8) Hematological§§§ 1 4 1 6 (1.5) Total 36 13 5 54 (13.8) Carriers can have more than one malformation or medical finding. Common medical conditions like upper airway infections, otitis media etc. were not included in the table or in the text below.

*Hemivertebra, segmentation anomaly, butterfly vertebra, flattening of corpus vertebra, supernummerary costa, fusion of costal cote, spondylolisthesis, costal malformation unspecified, sprengel deformity, radial hyppoplasia, humoradial fusion, ulnar agenesis, contractures in knees and ankles/arthrogyposis. **Structural heart defect include: atrial-/ventricular septum defect (n=9), congenital valvulopathy (n=1), aortic valve anomaly (n=1), pulmonary valve atresia (n=2), total anomalous pulmonary venous drainage (n=1), patent ductus arteriosus (n=4), complete atrioventricular canal defect (n=1), coarctation of aorta (n=2), tetralogy of Fallot (n=1), patent foramen ovale (n=2), dextrocardia (n=2), hypoplastic left heart/ hypoplastic right ventricle (n=2), unspecified structural heart defect (n=2). §Exophthalmos, enophthalmia, glaucoma, viral neuritis, recurrent conjunctivits, ptosis, iris inflammation, and chronic hordeolum catarrh. §§Kidney oncocytoma (n=1), urinary tract tumors unspecified (n=1), breast cancer (n=1). §§§Anemia, coagulopathies, thrombofilia, neutropenia.

Frequent or minor medical conditions not included in the table include: Visual disorder as strabism (n= 22), refractive errors (myopia, hypermetropia, astigmatism, amblyopia, achromatopsia, convergence insufficiency) (n=40), skin conditions (atopic dermatitis, eczema, xerosis, psoriasis, chronic urticaria, generalized keratosis, alopecia) (n=26), asthma (n=11), gastroesophagal reflux disease (n=6), celiac disease (n=3), constipation (n=9), inguinal/umbilical hernia (n=3), dysphagia (n=3), minor osteo-articular anomalies (pectus excavatum/pectus carniatum/pes planus/pes varus/pes valgus/joint

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Jønch et al. hypermobility/club feet/poly-, brachy-, clino-, syndactyly/ hip dislocation/subluxation) (n=61), delayed puberty (n=4), precocious puberty (n=2), Diabetes (n=2), Hypercholesterolemia (n=2), Hyperinsulinemia (n=2), Hypothyroidism (n=5), D-vitamin deficiency (n=3), heart murmur (n=4), arterial hypertension (n=5), hypotension (n=1), cardiac dysrhythmia (tachycardia, etc.)(n=3), infertility (n=3), severe obesity (n=5), postnatal +/-prenatal growth retardation (n=8), short stature (n=13), allergy (n=16).

Malformations occuring in a single proband or relative not included in the table: Inner ear abnormalities unspecified, proximal esophageal atresia and distal trecheoesophageal fistula, velopharyngeal incompetence, intraosseus epidermoid cyst, encephalocele, duplex kidney, urinary system anomaly unspecified, rectovaginal fistula, aberrant subclavian artery.

Medical conditions occuring in a single proband or relative not included in the table: Chronic sinusitis, chronic pansinuitis, absence of spontaneous ventilation, breathing problems unspecified, chronic lung disease, dyspnea, recurrent pneumothorax, Chronic Obstructive Lung Disease (COLD), apnea, abdominal migraines, complete digestive intolerance, lactose intolerance, irritable bowel disease, juvenile rheumatoid arthritis, delayed bone maturation, rachitis in childhood, hypochondroplasia, early onset arthritis, rickets, proximal tubulopathy Fanconi type, hypoimmunoglobulineamia, Hereditary Hemorrhagic Telangiectasia, hypogammaglobulinemia, hyperammonemia, hyperalbuminuria, hypercortisolemia, gonadotropin deficiency, multiple metabolic alterations (incl. hyponatremia glucosuria proteinuria hypercalciuria, hypomagnesemia, acidemia and aciduria, low glutaminemia, high aminoacid, low B2-vitamin), multinodular goiter, thoracic aortic aneurysm and aorta dissection, unexplained cardiac and respiratory arrest, fibromyalgia, ovary cysts.

+NDD, probands ascertained for neurodevelopmental disorders; -NDD, probands not ascertained for NDDs; n, number of cases

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Table S15. Malformation and medical conditions in 15q11.2 duplication carriers from the clinically referred group according to ascertainment

Probands Relatives All carriers DUPLICATION

Congenital malformation +NDD -NDD n=38 n= 214 (%) n=139 n=37 Cataracts/Retinal Ophthalmic dystrophia/Optic nerve 3 0 0 3 (1.4) atrophy Cleft +/- lip palate, submucous cleft, bifid Orofacial 2 7 1 10 (4.7) uvula, Pierre Robin sequence, choanal atresia Craniosynostosis, Craniofacial metopic ridges, 8-shaped 0 3 0 3 (1.4) head Vertebral anomalies, rib Osteo- anomalies, other osseous 2 5 0 7 (3.3) articular anomalies* Cardio- Structural heart defect** 3 7 0 10 (4.7) vascular Cardiomyopathy 0 1 1 2 (0.9) Diaphragmatic hernia, Digestive laryngeal web, pyloric 1 2 0 3 (1.4) stenosis Hydronephrosis, Urinary tract duplicated collecting 1 2 0 3 (1.4) system Cryptorchidism, hypoplastic scrotum, Genitalia 7 1 1 9 (4.2) hypospadia, variocele, spermatic cord cyst,

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Jønch et al. clitoris hypertrophy Total 20 27 3 50 (23.4) Medical conditions Blindness or reduced vision 4 0 0 4 (1.9) Other eye conditions§ 6 0 1 7 (3.3) Hearing impairment/deafness 7 3 1 11 (5.1) Scoliosis/kyphosis/lordosis/ torticollis 2 7 0 9 (4.2) Tumors§§ 1 1 0 2 (0.9) Total 19 11 2 32 (14.9) Carriers can have more than one malformation or medical finding. Common medical conditions like upper airway infections, otitis media etc. were not included in the table or in the text below.

*Structural heart defect includes: atrial septal defect (n=2), congenital valvulopathy (n=1), aortic dilatation/hypoplasia (n=2), pulmonary valve dysplasia (n=1), peripheral pulmonary stenosis (n=1), patent foramen ovale (n=1), Ebstein’s anomaly (n=1), unspecified heart defect (n=1). ** Segmentation anomaly, hemivertebra, 4 sacral vertebra, unspecified columna anomaly, clavicles high in the neck and narrow thorax, supernumerary costa, radial abnormality, absent fibula. §Nystagmus, dacrystenosis, ptosis, myadriasis, light sensitivity. §§Multiple myeloma (smoldering type), neuroblastoma.

Frequent or minor medical conditions not included in the table above: Visual disorder as strabism (n= 12), refractive errors (myopia, hypermetropia, astigmatism, amblyopia, achromatopsia, convergence insufficiency) (n=16), nystagmus (n=3), skin conditions (atopic dermatitis, eczema, xerosis, psoriasis, palmar erythroderma, hypertrichosis) (n=15), asthma (n=9), gastroesophagal reflux disease (n=4), dysphagia (n=1), celiac disease (n=1), constipation (n=3), minor osteo- articular anomalies (pectus excavatum/pectus carniatum/pes planus/pes varus/pes valgus/genu valgum/joint hypermobility/poly-, brachy-, clino-, syndactyly/hip dysplasia) (n=34), delayed puberty (n=2), hypercholesterolemia (n=2), hypothyroidism (n=2), hypercholesterolemia (n=2), hypertension (n=1), cardiac dysrhythmia (tachycardia etc.) (n=1), severe obesity (n=7), growth retardation (n=10), short stature (n=3), allergy (n=10), ovary cysts (n=2), sleep apnea syndrome (=3).

Malformations occurring in a single proband or relative not included in the table: Narrow ear canal, laryngeal webbing, digestive system anomaly unspecified, multicystic dysplastic left kidney.

Medical conditions occurring in a single proband or relative not included in the table:

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Jønch et al. Ichtyosis, Jeune syndrome, bronchopulmonary dysplasia, pneumothorax, reactive airway disease, reduced lung function, respiratory insufficiency unspecified, lactose intolerance, ulcerative colitis, cyclic vomiting, digestive and transit disorder, Calve Legg Perthes, hemifacial microsomia (n=2), chronic neutropenia, thalassemia, apolipoprotein C3 abnormality, benign thyroid nodule, ascending aortic aneurysm, recurrent breast cysts, severe oligospermi.

+NDD, probands ascertained for neurodevelopmental disorders; -NDD, probands not ascertained for NDDs; n, number of cases

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Jønch et al. Table S16. Comparing frequencies of ID in 15q11.2 deletion and duplication probands from the clinically referred group CNV Frequency %, No P-value (Del vs. Dup) All deletion probands 42.3 (138/326) 0.13 All duplication probands 35.2 (62/176) NDD-deletion probands 50 (133/266) 0.25 NDD-duplication probands 43.2 (60/139) Deletion probands* 43.1 (129/299) 0.14 Duplication probands* 35.6 (58/163) Deletion probands** 43.2 (126/292) 0.11 Duplication probands** 35.0 (56/160) *After removal of 27 deletion and 13 duplication probands with additional pathogenic CNVs. Among these cases 9 deletion and 4 duplication probands with an additional pathogenic CNV had a history of ID. **After removal of further 7 deletion and 3 duplication probands with additional pathogenic SNVs or chromosomal rearrangements from probands with additional pathogenic CNVs. 3 deletion and 2 duplication probands among these cases had a history of ID.

ID, intellectual disability; CNV, copy number variant; No, number of cases; Del, deletion; Dup, duplication; vs., versus; NDD, probands ascertained with neurodevelopmental disorders; SNVs, single nucleotide variants.

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