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



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 an 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.

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Fig. 1: Autosomal recessive copy-number variants (AR-CNVs) contribute to diseases by multiple ways.
Fig. 2: Characteristics of autosomal recessive copy-number variants (AR-CNVs).
Fig. 3: Different mechanisms of autosomal recessive copy-number variants (AR-CNVs) contributing to diseases in the current cohort.


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This study was partially supported by the National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant UM1HG006542 to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG); National Institute of Neurological Disorders and Stroke (NINDS) grant R35 NS105078-01 to J.R.L.

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Corresponding authors

Correspondence to Bo Yuan PhD or Weimin Bi PhD.

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Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), formerly the Baylor Miraca Genetics Laboratories (BMGL), which performs chromosomal microarray analysis and clinical exome sequencing. B.Y., P.L., C.S., H.D., L.M., Y.W., F.X., S.P., E.S., P.A.W., J.S., C.A.B., C.M.E., and W.B. are employees of BCM and derive support through a professional services agreement with BG. J.R.L. serves on the Scientific Advisory Board of the BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals and Novartis, has stock options in Lasergen, Inc. and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The other authors declare no conflicts of interest.

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Yuan, B., Wang, L., Liu, P. et al. CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels. Genet Med (2020).

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  • autosomal recessive
  • copy-number variants
  • SNV/indel
  • clinical molecular diagnoses
  • multiple molecular diagnoses