Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes

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).

Rare copy number variation in cerebral palsy

“…21 Results were also compared with the frequency of events in 337 National Institute of Mental Health (NIMH) controls analysed using the same 135K array. 25 DNA isolated from lymphoblastoid cell lines was used for CNV analyses, and DNA isolated from whole blood was used for subsequent CNV validations. Parental DNA was isolated from whole blood only.…”

“…The empirically determined detection resolution for this array was 450 kb within the hotspots and4350 kb in the genomic backbone. 25 All microarrays were analysed by mapping probe coordinates to the human genome assembly Build 36 (hg18). To minimise false positives on both array platforms, deletions and duplications were determined by a minimum of four consecutive probes beyond a mean significance log 2 ratio of À0.26 and 0.3, respectively.…”

“…25 Notably, all these CNVs were discovered using the same array design facilitating comparison across disease cohorts. CNV load in CP was similar to that in controls or the dyslexia cohort (Figure 1).…”

A genetic model for neurodevelopmental disease

“…Comparisons of CNV burden for different diseases suggest increasing CNV burden in disorders with greater phenotypic severity (defined here in terms of increasing comorbid cognitive impairment and congenital abnormalities) [1,19,20]. Cases with congenital malformations demonstrate the greatest increase in CNVs followed by ID/DD.…”

The recurrent distal 22q11.2 microdeletions are often de novo and do not represent a single clinical entity: a proposed categorization system

“…[1][2][3] The great majority of these recurrent CNVs are mediated by recombination between nonallelic homologous segmental duplications, also called low copy repeats (LCRs), through the well-established mechanism of nonallelic homologous recombination. 4 In recent years, the detection of these recurrent events has been facilitated by the wide use of cytogenomic arrays in clinical diagnostics.…”