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Defining the Effect of the 16P11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

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Defining the Effect of the 16P11.2 Duplication on Cognition, Behavior, and Medical Comorbidities Supplementary Online Content D’Angelo D, Lebon S, Chen Q, et al; Cardiff University Experiences of Children With Copy Number Variants (ECHO) study; 16p11.2 European Consortium; Simons Variation in Individuals Project (VIP) Consortium. Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities. JAMA Psychiatry. Published online December 2, 2015. doi:10.1001/jamapsychiatry.2015.2123. eMethods. Data Sources and Additional CNVs eResults. Malformations, Medical Problems, and Sex Differences eTable 1. Ascertainment of 16p11.2 Duplication and Deletion Carriers eTable 2. Effect of the Deletion on Global Intelligence and Anthropometric Measures eTable 3. Effect of the Duplication on Full-Scale IQ (FSIQ), Controlling for ASD and Seizures eTable 4. Effect of the Deletion on Full-Scale IQ (FSIQ), Controlling for ASD and Seizures eTable 5. Effect of the Duplication on Nonverbal IQ (NVIQ), Controlling for ASD and Seizures eTable 6. Effect of the Deletion on Nonverbal IQ (NVIQ), Controlling for ASD and Seizures eTable 7. Effect of the Duplication on Verbal IQ (VIQ), Controlling for ASD and Seizures eTable 8. Effect of the Deletion on Verbal IQ (VIQ), Controlling for ASD and Seizures eTable 9. Additional Deleterious CNVs in 16p11.2 Probands Carriers Excluded From the Main Analysis eTable 10. Duplication Inheritance Subanalysis eTable 11. Deletion Inheritance Subanalysis eTable 12. Neurologic Features in 16p11.2 Duplication Carriers According to Ascertainment eTable 13. Neurologic Features in 16p11.2 Deletion Carriers According to Ascertainment eTable 14. Behavioral and Psychiatric Features of 16p11.2 Duplication Carriers eTable 15. Behavioral and Psychiatric Features of 16p11.2 Deletion Carriers eTable 16. Effect of the Duplication on Body Mass Index (BMI) z Score, Controlling for ASD, Seizures, and NVIQ eTable 17. Effect of the Deletion on Body Mass Index (BMI) z Score, Controlling for ASD, Seizures, and NVIQ eTable 18. Effect of the Duplication on Head Circumference (HC) z Score, Controlling for ASD, Seizures, and NVIQ eTable 19. Effect of the Deletion on Head Circumference (HC) z Score, Controlling for ASD, Seizures, and NVIQ eTable 20. Major Malformations and Medical Problems in 16p11.2 Duplication Carriers According to Ascertainment eTable 21. Major Malformations and Medical Problems in 16p11.2 Deletion Carriers According to Ascertainment eTable 22. Duplication Carriers With Multiple Medical Conditions According to Ascertainment eTable 23. Deletion Carriers With Multiple Medical Conditions According to Ascertainment eFigure 1. Distribution of IQ Scores by Region eFigure 2. Full-Scale IQ (FSIQ) in Probands Stratified by Site, Sex, Seizure Status, and HC z Score Above vs Below 0 eFigure 3. Distribution of Additional Deleterious CNVs by Size and Their Numbers of Protein-Coding Genes Included in Duplication and Deletion Carriers eFigure 4. FSIQ of Inherited and De Novo Duplication and Deletion Probands vs Parent FSIQ eFigure 5. Age of Walking in Duplication Proband Carriers vs Deletion Proband Carriers This supplementary material has been provided by the authors to give readers additional information about their work. © 2015 American Medical Association. All rights reserved. 1 Downloaded From: https://jamanetwork.com/ on 10/01/2021 eMethods. Data Sources and Additional CNVs Data sources: Clinical information was collected for a total of 270 duplication carriers ascertained through different cohorts, and 102 of their familial non-carrier controls. Ascertainment of duplication carriers is summarized in Table S1. Most probands were ascertained on the basis of a neurodevelopmental disorder (ND) including developmental delay/intellectual disability (DD/ID) or autism spectrum disorder (ASD) and were identified through genetic testing performed for clinical diagnostic purposes. In a few cases, ascertainment was based on a specific psychiatric diagnosis (schizophrenia or bipolar affective disorder) as well as genotyping of a general population cohort (Estonian Genome Center, University of Tartu: EGCUT).1,2 Individuals were recruited from the 16p11.2 European consortium, the Cardiff University ECHO study in the UK and Simons VIP in the United States, as well as other genetic centers or previously published studies.3-10 All data (including literature) were grouped into EU and USA cohorts for statistical analysis. Deletion carrier comparison group: A sample of 390 16p11.2 deletion carriers (Table S1), some of which were previously published,11 was available for comparison. Data for full-scale intelligence quotient (FSIQ), non- verbal IQ (NVIQ) or verbal IQ (VIQ) were available for n=200, n=205 and n=184 deletion carriers, respectively. These data were compared to n=242, n=242 and n=230 of their intrafamilial controls, respectively. Additional CNVs: Data on additional deleterious CNVs were available for probands ascertained for NDs. Information on these additional variants was provided by different diagnostic platforms with varying resolution (eg. Agilent 44K, 105K, 180K, 244K, 250K; Affymetrix 250K, Illumina Human370CNV and Human OMNIExpress). The group of 142 duplication probands ascertained for NDs (Table S1) was obtained after exclusion of 16 duplication probands carrying an additional deleterious CNV (10.1% second hit rate). The group of 283 deletion probands ascertained for NDs (Table S1) was obtained after exclusion of 15 deletion probands carrying an additional deleterious CNV (5.0% second hit rate) (Supplementary Table S9). We used an independent replication dataset from Signature Genomics showing with 7/65 (10.7%) and 3/107 (2.8%) of additional deleterious CNV in duplication and deletion carriers ascertained for NDs, respectively. © 2015 American Medical Association. All rights reserved. 2 Downloaded From: https://jamanetwork.com/ on 10/01/2021 eResults. Malformations, Medical Problems, and Sex Differences Malformations and medical problems Major malformations are present in 16.7% (30/180) of duplication probands. Among these 30 probands, 17 had one and 13 had two or more malformations. In relatives, 9/90 (10.0%) have major malformations which are isolated in all cases except one. In probands and relatives ascertained for NDs major malformations are present in 21.6% (24/111) and 10.6% (9/85) of EU and the VIP duplication carriers respectively. Scoliosis, genital and cardiac malformations and are the most frequent medical conditions in duplications (Supplementary Tables S20 and S21). Magnetic resonance imaging (MRI) of the brain in a subset of 86 duplication carriers showed cerebellar hypoplasia and enlarged ventricles as the most frequent findings (15.1% and 11.6%, respectively, Supplementary Table S12). Characteristic facial dysmorphism is absent in duplication carriers. In comparison, major malformations are present in 67/317 (21.1%) deletion proband carriers. Among these 67 probands, 42 had one and 25 had two or more malformations. In relatives, 8/73 (11.0%) have major malformations, four had one and four had two malformations. Like, duplication carriers, scoliosis (secondary to vertebral anomalies in 42.1%), genital and cardiac malformations are the most frequent medical conditions in deletion carriers (Supplementary Table S22). Brain malformations/anomalies are observed in 49.0% (53/108) of a subset of 108 deletion carriers and mainly involve posterior fossa (36/108, 33.3%); among them 11 carriers had Chiari I malformation (11/36, 30.6%, Supplementary Table S13). © 2015 American Medical Association. All rights reserved. 3 Downloaded From: https://jamanetwork.com/ on 10/01/2021 Sex differences We used the Binomial test to assess the equality of gender proportions in each ascertainment group in supplementary Table S1. There are significantly more males among duplication probands (p=0.04), and this is driven by carriers ascertained for NDs (p=0.001). A similar pattern is observed for deletion proband carriers ascertained for NDs (p<0.001). There is no gender difference in other carrier groups. Among duplication families, gender had a significant effect on nonverbal IQ (p=0.04), with males having an average 4-point increase over females. There was no significant effect of gender on verbal IQ (p=0.78), full-scale IQ (p=0.42), BMI z score (p=0.69) or head circumference (HC) z score (p=0.25) (Table 3). In deletion families, there was a similar effect of gender on nonverbal IQ with males higher than females by an average of 3 points (p=0.02). Gender additionally had a significant effect on HC z score, with males having larger average z scores (p<0.001) (Table S2). There was a marginally significant effect of gender on full-scale IQ, again with males higher (p=0.06), but no significant effect on verbal IQ (p=0.71) or BMI z score (p=0.13). © 2015 American Medical Association. All rights reserved. 4 Downloaded From: https://jamanetwork.com/ on 10/01/2021 eReferences 1. Firmann M, Mayor V, Vidal PM, et al. The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC cardiovascular disorders 2008; 8: 6. 2. Leitsalu L, Haller T, Esko T, et al. Cohort Profile: Estonian Biobank of the Estonian Genome Center, University of Tartu. International journal of epidemiology 2014. 3. Weiss LA, Shen Y, Korn JM, et al. Association between microdeletion and microduplication at 16p11.2 and autism. The New England journal of medicine 2008; 358(7): 667-75. 4. McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nature genetics 2009; 41(11): 1223-7. 5. Shinawi M, Liu P, Kang SH, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of medical genetics 2010; 47(5): 332-41. 6. Fernandez BA, Roberts W, Chung B, et al. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. Journal of medical genetics 2010; 47(3): 195-203. 7. Bedoyan JK, Kumar RA, Sudi J, et al. Duplication 16p11.2 in a child with infantile seizure disorder.
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