Clinical detection of deletion structural variants in whole-genome sequences

• Published in: Npj genomic medicine 2016-08, Vol.1 (1), p.16026-16026, Article 16026
• Main Authors: Noll, Aaron C, Miller, Neil A, Smith, Laurie D, Yoo, Byunggil, Fiedler, Stephanie, Cooley, Linda D, Willig, Laurel K, Petrikin, Josh E, Cakici, Julie, Lesko, John, Newton, Angela, Detherage, Kali, Thiffault, Isabelle, Saunders, Carol J, Farrow, Emily G, Kingsmore, Stephen F
• Format: Article
• Language: English
• Subjects: 631/114/2785; 692/4017; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Gene Function; Gene Therapy; Human Genetics; Internal Medicine
• ISSN: 2056-7944; 2056-7944
• DOI: 10.1038/npjgenmed.2016.26

Optimal management of acutely ill infants with monogenetic diseases requires rapid identification of causative haplotypes. Whole-genome sequencing (WGS) has been shown to identify pathogenic nucleotide variants in such infants. Deletion structural variants (DSVs, >50 nt) are implicated in many genetic diseases, and tools have been designed to identify DSVs using short-read WGS. Optimisation and integration of these tools into a WGS pipeline could improve diagnostic sensitivity and specificity of WGS. In addition, it may improve turnaround time when compared with current CNV assays, enhancing utility in acute settings. Here we describe DSV detection methods for use in WGS for rapid diagnosis in acutely ill infants: SKALD (Screening Konsensus and Annotation of Large Deletions) combines calls from two tools (Breakdancer and GenomeStrip) with calibrated filters and clinical interpretation rules. In four WGS runs, the average analytic precision (positive predictive value) of SKALD was 78%, and recall (sensitivity) was 27%, when compared with validated reference DSV calls. When retrospectively applied to a cohort of 36 families with acutely ill infants SKALD identified causative DSVs in two. The first was heterozygous deletion of exons 1–3 of MMP21 in trans with a heterozygous frame-shift deletion in two siblings with transposition of the great arteries and heterotaxy. In a newborn female with dysmorphic features, ventricular septal defect and persistent pulmonary hypertension, SKALD identified the breakpoints of a heterozygous, de novo 1p36.32p36.13 deletion. In summary, consensus DSV calling, implemented in an 8-h computational pipeline with parameterised filtering, has the potential to increase the diagnostic yield of WGS in acutely ill neonates and discover novel disease genes. Genomic testing: Identifying disease-causing DNA deletion A new method that detects parts of the genome where chunks of DNA are missing could aid the rapid diagnosis of serious genetic disorders. These DNA deletions, as they are known, are implicated in many genetic diseases, and although techniques exist to spot them, there is no gold standard clinical test. Stephen Kingsmore and colleagues from the Rady Children’s Institute for Genomic Medicine in San Diego and Children’s Mercy Hospital in Kansas City have devised a new method that incorporates whole genome sequence data and two already-existing techniques. The result is a test with good predictive value that was able to detect dise