Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

Abstract

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

1q21.1 Microduplication expression in adults

“…[17][18][19][20] Other citations involving 1q21.1 duplication cases were also assessed. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] Cases of 1q21.1 duplication in GeneReviews (http://www.ncbi.nlm. nih.gov/books/NBK52787) and the four references provided therein 1,2,10,25 were reviewed as well, but no new subjects or phenotypic data were identified.…”

“…3,35 We systematically reviewed 28 primary reports identified and their accompanying supplemental materials to identify unique individuals and abstract as much information as possible on each subject. 1,2,[5][6][7][8][9][10][11][12][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Any subjects with 1q21.1 duplications that were not 1.0-5.0 Mb (Figure 1) in size were excluded, 12,31 allowing us to include atypical variants that were larger or smaller than the standard duplication classes used in our analyses. We documented the ascertainment criteria, country of origin, authors, and the demographic, clinical, and genotypic characteristics of subjects in different studies, and used these variables to attempt to identify duplicate cases reported in two or more papers.…”

“…Four studies were excluded because the sources of subjects overlapped with those of other reports and/or the origin of cases was not specified. 17,18,32,34 We compiled data for 107 subjects from the remaining 22 studies 1,2,[5][6][7][8][9][10][11][19][20][21][22][23][24][25][26][27][28][29][30]33 for the main analyses in this report.…”

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…1,2 Recent studies have demonstrated that ASDs can be caused by rare, highly penetrant point mutations, deletions, duplications and larger chromosomal abnormalities that can either arise de novo or be inherited. [3][4][5][6][7][8][9] Known monogenic disorders account for 2-5% of syndromic cases; fragile X syndrome is usually the most common cause, followed by PTEN macrocephaly syndrome and tuberous sclerosis, each accounting for o1% of individuals with ASD. 1,10 Large copy number variants (CNVs) are found in 5-10% of autistic patients, especially in those with syndromic ASDs.…”

Copy number variation in patients with cervical artery dissection

“…5 Rare copy number variants (CNVs) have a role in the etiology of tetralogy of Fallot, sporadic epilepsy syndromes or autism. [6][7][8] In patients with sporadic aortic aneurysms and dissections rare CNVs were identified that disrupt genes involved in vascular smooth muscle function. 9 The current study was the first analysis of CNVs in CeAD.…”