Clinical analysis of germline copy number variation in DMD using a non-conjugate hierarchical Bayesian model

Abstract

BackgroundDetection of copy number variants (CNVs) is an important aspect of clinical testing for several disorders, including Duchenne muscular dystrophy, and is often performed using multiplex ligation-dependent probe amplification (MLPA). However, since many genetic carrier screens depend instead on next-generation sequencing (NGS) for wider discovery of small variants, they often do not include CNV analysis. Moreover, most computational techniques developed to detect CNVs from exome sequencing data are not suitable for carrier screening, as they require matched normals, very large cohorts, or extensive gene panels.MethodsWe present a computational software package, geneCNV (http://github.com/vkozareva/geneCNV), which can identify exon-level CNVs using exome sequencing data from only a few genes. The tool relies on a hierarchical parametric model trained on a small cohort of reference samples.ResultsUsing geneCNV, we accurately inferred heterozygous CNVs in the DMD gene across a cohort of 15 test subjects. These results were validated against MLPA, the current standard for clinical CNV analysis in DMD. We also benchmarked the tool’s performance against other computational techniques and found comparable or improved CNV detection in DMD using data from panels ranging from 4,000 genes to as few as 8 genes.ConclusionsgeneCNV allows for the creation of cost-effective screening panels by allowing NGS sequencing approaches to generate results equivalent to bespoke genotyping assays like MLPA. By using a parametric model to detect CNVs, it also fulfills regulatory requirements to define a reference range for a genetic test. It is freely available and can be incorporated into any Illumina sequencing pipeline to create clinical assays for detection of exon duplications and deletions.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0404-4) contains supplementary material, which is available to authorized users.

Exonic copy number variations in rare genetic disorders

“…Numerous well-established genes, such as DMD [4,5] and SMN1 [6,7], have been documented for exonic CNVs. In this section, our objective is to investigate CNVs that are comparatively less familiar but recurrently reported in scientific literature.…”

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

“…Therefore, detecting CNVs precisely on exon level is highly important in the case of dystrophinopathies. This is quite feasible from NGS data, with separate approaches developed specifically for analyzing CNVs in the gene DMD due to its high clinical significance, but more general approaches have provided detections as well [114,115].…”