CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.

TitleCNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.
Publication TypeJournal Article
Year of Publication2020
AuthorsYuan, 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, DM, Gibbs, RA, Beaudet, AL, Breman, AM, Smith, J, Cheung, SWai, Bacino, CA, Eng, CM, Yang, Y, Lupski, JR, Bi, W
JournalGenet Med
Volume22
Issue10
Pagination1633-1641
Date Published2020 10
ISSN1530-0366
KeywordsChild, DNA Copy Number Variations, Exons, Humans, INDEL Mutation, Retrospective Studies, Whole Exome Sequencing
Abstract

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.

DOI10.1038/s41436-020-0864-8
Alternate JournalGenet Med
PubMed ID32576985
Grant ListT32 OD011089 / OD / NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States