Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes

• Published in: European journal of human genetics : EJHG Vol. 32; no. 8; pp. 998 - 1004
• Main Authors: Demidov, German, Laurie, Steven, Torella, Annalaura, Piluso, Giulio, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Graessner, Holm, Banka, Siddharth, Lohmann, Katja, Ossowski, Stephan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.08.2024; Springer International Publishing
• Subjects: Breakpoints; DNA Copy Number Variations; Exome - genetics; Exome Sequencing; Genetic Testing - methods; Genetic Testing - standards; Genomic Structural Variation; Humans; Rare diseases; Rare Diseases - diagnosis; Rare Diseases - genetics; Translocation; Whole genome sequencing
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-024-01637-4

Structural variants (SVs), including large deletions, duplications, inversions, translocations, and more complex events have the potential to disrupt gene function resulting in rare disease. Nevertheless, current pipelines and clinical decision support systems for exome sequencing (ES) tend to focus on small alterations such as single nucleotide variants (SNVs) and insertions-deletions shorter than 50 base pairs (indels). Additionally, detection and interpretation of large copy-number variants (CNVs) are frequently performed. However, detection of other types of SVs in ES data is hampered by the difficulty of identifying breakpoints in off-target (intergenic or intronic) regions, which makes robust identification of SVs challenging. In this paper, we demonstrate the utility of SV calling in ES resulting in a diagnostic yield of 0.4% (23 out of 5825 probands) for a large cohort of unsolved patients collected by the Solve-RD consortium. Remarkably, 8 out of 23 pathogenic SV were not found by comprehensive read-depth-based CNV analysis, resulting in a 0.13% increased diagnostic value.