Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders

Abstract

Purpose:Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a first-tier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10–20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome- or genome-wide approach with a single test.Methods:We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting.Results:In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of ~2% (ranging from 0 to –5.8% per disorder).Conclusions:This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.Genet Med advance online publication 27 October 2016

A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1

“…Indeed, recent studies showed that exonic CNVs play an important role in a broad range of genetic disorders, accounting for a considerable number of disease‐alleles (Gambin et al, ; Pfundt et al, ). In muscle disorders, intragenic deletions were found to represent about 6% of the disease‐variants (Pfundt et al, ). Therefore, this case indicates that the integrated CNVs and variants analysis could be offered also in prenatal diagnosis of selected cases.…”

The Role of Copy Number Variants in Disorders of Sex Development

“…No relevant CNVs were detected in this DSD patient cohort, possibly due to the focus on coding regions. However, this research highlights the importance of investigating the role CNVs play in genetic disease and moves the field closer to a single genomics test [Pfundt et al, 2017]. Whole genome sequencing (WGS) has the potential to make all other techniques discussed in this review obsolete.…”

“…Only within the last year has WES successfully been able to detect CNVs in other human disease studies with acceptable reliability [Gambin et al, 2016;Jo et al, 2016], although the precision of the data analysis pipelines is currently less than 80% when comparing large cohorts [Gambin et al, 2016]. Recently a study using WES to screen 2,603 patients with a range of genetic disorders, including 38 DSD patients, showed that on average each patient had 6 CNVs throughout their genome [Pfundt et al, 2017]. Across the entire patient cohort, WES successfully detected 123 clinically relevant CNVs with definitive diagnosis in 51 cases.…”

The combination of whole‐exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders

“…10 Various strategies including biopsies, karyotype, chromosomal microarray analysis (CMA), Sanger sequencing, and multiplex ligationdependent probe amplification (MLPA) were developed to elucidate the molecular etiologies. 12 [14][15][16] However, to the best of our knowledge, studies of diagnostic yields using comprehensive detection of CNVseq and other NGS strategies are rarely reported. 11 In addition, only specific genes can be identified, while novel pathogenic genes cannot be detected.…”