Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles

Abstract

Over 1200 recessive disease genes have been described in humans. The prevalence, allelic architecture, and per-genome load of pathogenic alleles in these genes remain to be fully elucidated, as does the contribution of DNA copy-number variants (CNVs) to carrier status and recessive disease. We mined CNV data from 21,470 individuals obtained by array-comparative genomic hybridization in a clinical diagnostic setting to identify deletions encompassing or disrupting recessive disease genes. We identified 3212 heterozygous potential carrier deletions affecting 419 unique recessive disease genes. Deletion frequency of these genes ranged from one occurrence to 1.5%. When compared with recessive disease genes never deleted in our cohort, the 419 recessive disease genes affected by at least one carrier deletion were longer and located farther from known dominant disease genes, suggesting that the formation and/or prevalence of carrier CNVs may be affected by both local and adjacent genomic features and by selection. Some subjects had multiple carrier CNVs (307 subjects) and/or carrier deletions encompassing more than one recessive disease gene (206 deletions). Heterozygous deletions spanning multiple recessive disease genes may confer carrier status for multiple single-gene disorders, for complex syndromes resulting from the combination of two or more recessive conditions, or may potentially cause clinical phenotypes due to a multiply heterozygous state. In addition to carrier mutations, we identified homozygous and hemizygous deletions potentially causative for recessive disease. We provide further evidence that CNVs contribute to the allelic architecture of both carrier and recessive disease-causing mutations. Thus, a complete recessive carrier screening method or diagnostic test should detect CNV alleles.

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

“…Genome-wide approaches have shown that rare variants are more common than previously thought [Coventry et al, 2010; Marth et al, 2011]; a robust observation for both SNV and CNV disease associated alleles [Boone et al, 2013]. The overall phenotype of a given individual may to a greater extent represent contribution of either de novo or more recent and private mutational events with bigger effects on the whole system function, the ‘driver’ genes that occurred in the recent ancestors of the individual or clan [Lupski et al, 2011], rather than more distributed common variants shared in a population or throughout several populations.…”

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

“…Deletions would lead to a hemizygous allele at corresponding genomic regions and contribute to the allelic architecture of both carrier and recessive disease-causing mutations (Boone et al 2013; Flipsen-ten Berg et al 2007). The recent report of a compound inheritance model in congenital scoliosis (CS) provides a model to simulate this particular scenario (Wu et al 2015).…”

Exome sequencing and whole genome sequencing for the detection of copy number variation

“…However, the role of CNVs in most of these other disorders is unknown. It has been reported that CNVs contribute to 15% of both non-syndromic deafness [65] and retinal dystrophies [66,67], approximately 10% of congenial heart disease [68], partly because CNVs can often be identified in known recessive disease genes [18]. Traditionally, these disorders do not include CNV screening as part of their standard clinical practice and focus primarily on SNV and InDel detection.…”

“…The current generation of genomic microarrays contain hundreds-of-thousands to millions of probes that are able to detect CNVs ranging in size from 1 to 10 kilobases (kb) up to several megabases [7]. Many smaller pathogenic (intragenic) CNVs are known to occur but often remain beyond the detection limit of most clinical genomic microarray analyses [18,19].…”