Genetics in Medicine Features Baylor Genetics for Study on Autosomal Recessive Genetic Diseases

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

Bo Yuan, Lei Wang, Pengfei Liu Chad Shaw, Hongzheng Dai, Lance Cooper, Wenmiao Zhu, Stephanie A. Anderson, Linyan Meng, Xia Wang, Yue Wang, Fan Xia, Rui Xiao, Alicia Braxton, Sandra Peacock, Eric Schmitt, Patricia A. Ward, Francesco Vetrini, Weimin He, Theodore Chiang, Donna Muzny, Richard A. Gibbs, Arthur L. Beaudet, Amy M. Breman, Janice Smith, Sau Wai Cheung, Carlos A. Bacino  Christine M. Eng, Yaping Yang, James R. Lupski, Weimin Bi

Published: June 24, 2020 



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.


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.


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 a SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses.


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.

Genetics in Medicine (2020) 

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