|Title||CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Yuan, B, Wang, L, Liu, P, Shaw, C, Dai, H, Cooper, L, Zhu, W, Anderson, SA, Meng, L, Wang, X, Wang, Y, Xia, F, Xiao, R, Braxton, A, Peacock, S, Schmitt, E, Ward, PA, Vetrini, F, He, W, Chiang, T, Muzny, D, Gibbs, RA, Beaudet, AL, Breman, AM, Smith, J, Cheung, SWai, Bacino, CA, Eng, CM, Yang, Y, Lupski, JR, Bi, W|
|Date Published||2020 10|
|Keywords||Child, DNA Copy Number Variations, Exons, Humans, INDEL Mutation, Retrospective Studies, Whole Exome Sequencing|
PURPOSE: Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort.
METHODS: We retrospectively investigated the CNVs' contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders.
RESULTS: CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3% of AR-CNVs affected one gene; among these 41.4% were single-exon and 35.0% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses.
CONCLUSIONS: AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.
|Alternate Journal||Genet Med|
|Grant List||T32 OD011089 / OD / NIH HHS / United States |
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States