Fine-Scale Survey of X Chromosome Copy Number Variants and Indels Underlying Intellectual Disability

Abstract

Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-density oligonucleotide X chromosome array platform. We identified pathogenic copy number variants in 10% of families, with mutations ranging from 2 kb to 11 Mb in size. The challenge of assessing causality was facilitated by prior knowledge of XLID-associated genes and the ability to test for cosegregation of variants with disease through extended pedigrees. Fine-scale analysis of rare variants in XLID families leads us to propose four additional genes, PTCHD1, WDR13, FAAH2, and GSPT2, as candidates for XLID causation and the identification of further deletions and duplications affecting X chromosome genes but without apparent disease consequences. Breakpoints of pathogenic variants were characterized to provide insight into the underlying mutational mechanisms and indicated a predominance of mitotic rather than meiotic events. By effectively bridging the gap between karyotype-level investigations and X chromosome exon resequencing, this study informs discussion of alternative mutational mechanisms, such as noncoding variants and non-X-linked disease, which might explain the shortfall of mutation yield in the well-characterized International Genetics of Learning Disability (IGOLD) cohort, where currently disease remains unexplained in two-thirds of families.

Diagnostic yield of array comparative genomic hybridization in adults with autism spectrum disorders

“…A recent fine-scale survey of X-chromosome CNVs verified that the duplication including CRLF2 and CSF2RA has been excluded from disease causation by segregation analysis. 31 There are a few similar duplications in DGV in the general population. Therefore, this CNV probably represents a rare polymorphism and was classified as a VUS, likely benign.…”

Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

“…figure likely underestimates the general contribution of sequence variants to XLID given the subjects were selected from a pool that had had previous clinical and molecular genetic screening. 30 …”

“…Some laboratories offer chromosome-specific arrays (eg, for nonsyndromic X-linked ID [XLID]). 30 The primary advantage of CMA over the standard karyotype or later FISH techniques is the ability of CMA to detect DNA copy changes simultaneously at multiple loci in a genome in one "experiment" or test. The copy number change (or copy number variant [CNV]) may include deletions, duplications, or amplifications at any locus, as long as that region is represented on the array.…”

Facilitating Autism Research

“…Rare mutations have been identified in synapse-related genes, and genome-wide association (GWA) studies using single nucleotide polymorphisms have highlighted potential ASD risk loci on multiple chromosomes (Chaste et al, 2015), accounting for a small proportion of cases. CNVs, both de novo and familial, have been identified in 5-10% of individuals with ASD (Marshall et al, 2008;Sebat et al, 2007), which is a much higher rate than in the general population (1%), but not higher than in the ID population (Whibley et al, 2010). Some of the newly discovered CNVs contribute to neuronal migration and synaptic function but their presence in some unaffected family members (approximately 3%) leaves their contribution to autism uncertain (Gilman et al, 2011;Persico and Napolioni, 2013).…”