Response to Brodehl et al.

ClinSV: Clinical grade structural and copy number variant detection from whole genome sequencing data

“…Furthermore, ClinSV enables the identification of copy-number-neutral SVs and overlapping DEL-DUP events [10]. Ultimately these results were used to support the (Fig.…”

“…Absolute DOC measurements from WGS provide an advantage over relative quantification used in aCGH to accurately resolve the copy number level of regions frequently altered in the general population, often co-coinciding with multi-allelic CNV, which can include genes that are relevant to disease [58]. In support of this high clinical utility, ClinSV has been used in a number of research studies, which have identified short, pathogenic CNV affecting single exons [11], overlapping whole-gene deletion-duplications [10], and in adult patients with mitochondrial disease ( interpretation, it should be noted that the clinical interpretations in the issued pathology reports were performed prior to the publication of these guidelines and were instead based on a combination of previous guidelines [49,50]. When combined with segregation analysis using additional family members, there are typically fewer than 10 variants to inspect.…”

“…Until recently, WGS analytical methods had imperfect sensitivity and specificity for detection of SVs, leading some groups to report that SV detection from WGS was not yet fit for use in clinical practice [8,9]. There are now numerous recent reports using WGS to identify short CNV, affecting single genes, or even single exons as the cause of many monogenic disorders, suggesting considerable potential for short CNVs below the limit of detection of traditional MA to explain a proportion of previously undiagnosed patients [4,10,11]. The ability to find short, potentially pathogenic CNVs raises significant new interpretation challenges, as there are thousands of benign short CNVs in healthy individuals [12,13].…”

“…ClinSV also allows joint variant calling of multiple samples, so if pedigree information is provided, variants that are associated with only affected individuals can be readily identified. If a set of candidate genes is supplied, this set is further reduced; for example, in ~100 familial dilated cardiomyopathy genes, on average only 0.5 rare SVs were identified per patient[10]. Finally, ClinSV annotates variants using OMIM and Orphanet terms which can be useful to prioritize variants in patients' with challenging phenotypes.ClinSV output files: ClinSV produces a text file of all annotated CNVs and SVs, and a smaller file with just the rare, gene-affecting CNVs and SVs (Suppl.…”

The role of noncoding genetic variants in cardiomyopathy

“…Although definitive causative genetic mutations have been identified for familial cardiomyopathies, in over half of the cases targeted genetic screening tests do not identify a contributing variant. This is because most of the current clinical genetic screening tests and earlier research studies relied heavily on whole exome sequencing (WES) or targeted sequencing of coding regions (45,53,54). Another explanation regarding the lack of focus in noncoding variants is that even in large meta-analyses, the power of variant detection is limited by variant frequency and penetrance, and lack of systemic interpretation.…”