Abstract
While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID–associated phenotypes compared to autism (p = 9.58×10−11, odds ratio = 4.59), dyslexia (p = 3.81×10−18, odds ratio = 14.45), or controls (p = 2.75×10−17, odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4×10−6, odds ratio = 6) or ID (16%, p = 3.55×10−12, odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).
Highlights
Recent studies have implicated large, rare copy number variants (CNVs) in a range of neurodevelopmental disorders including intellectual disability (ID) [1,2], autism [3,4], schizophrenia [5,6], bipolar disorder [7,8], epilepsy [9,10], and attention deficit hyperactivity disorder (ADHD) [11,12]
We analyzed 1,227 individuals ascertained for three neurodevelopmental disorders: 376 dyslexic children with a verbal IQ (VIQ) $90 on the Wechsler Intelligence Scale for Children [13] and dyslexia defined as poor performance and IQ-performance discrepancy in one or more of a set of standardized reading
We observed striking differences in CNV burden and inheritance characteristics among these cohorts and show that ID is the primary correlate of large CNV burden
Summary
Recent studies have implicated large, rare CNVs in a range of neurodevelopmental disorders including intellectual disability (ID) [1,2], autism [3,4], schizophrenia [5,6], bipolar disorder [7,8], epilepsy [9,10], and attention deficit hyperactivity disorder (ADHD) [11,12]. Several themes have emerged from these studies: first, a significant enrichment for rare CNVs in individuals with the disease compared to unaffected controls was observed, independently, for each of these disorders; second, the same recurrent CNVs are associated with different neuropsychiatric phenotypes; and third, locus heterogeneity is substantial as many distinct variants can lead to similar phenotypes. Our understanding of the relevance of rare CNVs across a broad spectrum of neurodevelopmental disorders, varying in severity and prevalence, is limited as previous studies were restricted to the analysis of one phenotype at a time and each of such studies was performed using different CNV genotyping methodologies with distinct platform-specific biases, making comparisons difficult. We undertook a systematic analysis of 1,227 cases and 337 controls to assess the relative contribution of CNVs in three phenotypically distinct neurodevelopmental disorders. We designed a whole-genome custom microarray targeted to genomic hotspots for comparative genomic hybridization (CGH) to identify potentially pathogenic CNVs that contribute to ID, autism, and dyslexia
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