Dataset Information

A large data resource of genomic copy number variation across neurodevelopmental disorders.

ABSTRACT: Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

SUBMITTER: Zarrei M

PROVIDER: S-EPMC6779875 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A large data resource of genomic copy number variation across neurodevelopmental disorders.

Zarrei Mehdi M Burton Christie L CL Engchuan Worrawat W Young Edwin J EJ Higginbotham Edward J EJ MacDonald Jeffrey R JR Trost Brett B Chan Ada J S AJS Walker Susan S Lamoureux Sylvia S Heung Tracy T Mojarad Bahareh A BA Kellam Barbara B Paton Tara T Faheem Muhammad M Miron Karin K Lu Chao C Wang Ting T Samler Kozue K Wang Xiaolin X Costain Gregory G Hoang Ny N Pellecchia Giovanna G Wei John J Patel Rohan V RV Thiruvahindrapuram Bhooma B Roifman Maian M Merico Daniele D Goodale Tara T Drmic Irene I Speevak Marsha M Howe Jennifer L JL Yuen Ryan K C RKC Buchanan Janet A JA Vorstman Jacob A S JAS Marshall Christian R CR Wintle Richard F RF Rosenberg David R DR Hanna Gregory L GL Woodbury-Smith Marc M Cytrynbaum Cheryl C Zwaigenbaum Lonnie L Elsabbagh Mayada M Flanagan Janine J Fernandez Bridget A BA Carter Melissa T MT Szatmari Peter P Roberts Wendy W Lerch Jason J Liu Xudong X Nicolson Rob R Georgiades Stelios S Weksberg Rosanna R Arnold Paul D PD Bassett Anne S AS Crosbie Jennifer J Schachar Russell R Stavropoulos Dimitri J DJ Anagnostou Evdokia E Scherer Stephen W SW

NPJ genomic medicine 20191007

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed ...[more]

PMID: 31602316

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Project description:Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR?=?2.59; p?=?0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR?=?5.62; p?=?0.0002), but not in females (OR?=?1.19, p?=?0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR?=?2.59; p?=?0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.

Dataset Information

A large data resource of genomic copy number variation across neurodevelopmental disorders.

Publications

A large data resource of genomic copy number variation across neurodevelopmental disorders.

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