Abstract
BackgroundExome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.MethodsIn a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.ResultsThe QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.ConclusionsOur clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.
Highlights
Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels
Our clinical genomics study demonstrates that detection of Pathogenic/likely pathogenic copy number variants (CNVs) (PCNV)/uniparental disomy (UPD) through the quality control (QC) array or Chromosomal microarray analysis (CMA) increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses
Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and is recommended especially in time-sensitive clinical situations
Summary
Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. Copy number variants (CNVs), ranging in size from 50 to 100 bp to several megabases, are the direct cause of genomic disorders and are an underlying contributing genetic factor in both dominant or recessive human diseases, as well as complex traits [1,2,3,4,5]. More recent studies suggest that the detection rate for pathogenic CNVs is ~ 10% for clinical CMA with CNV interpretation based on the American College of Medical Genetics and Genomics (ACMG) criteria [11]. In another study using an ultrahigh-resolution microarray in 5487 patients, overall CNV diagnostic yield was as high as 29.4%, but 9.2% were pathogenic findings whereas 20.2% were variants of unknown significance; the most frequent pathogenic CNV is the 15q11.2 BP1-BP2 deletion detected in 31 patients [12]. The pathogenic CNV detection rate of this study would drop to 8.6% if this deletion is classified as being of unknown significance
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