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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.

SUBMITTER: Boone PM

PROVIDER: S-EPMC3759716 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Boone Philip M PM Campbell Ian M IM Baggett Brett C BC Soens Zachry T ZT Rao Mitchell M MM Hixson Patricia M PM Patel Ankita A Bi Weimin W Cheung Sau Wai SW Lalani Seema R SR Beaudet Arthur L AL Stankiewicz Pawel P Shaw Chad A CA Lupski James R JR

Genome research 20130516 9

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 iden ...[more]

PMID: 23685542

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Project description:BackgroundIn medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics.MethodsWe constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions.ResultsWe present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A.ConclusionsOur results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology.

Dataset Information

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

Publications

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

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