Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility

• DOI: 10.1371/journal.pgen.1010889
• Publication Date: 2023-08-14T17:26:57Z
• Authors: Timo A. Kumpula; Sandra Vorimo; Taneli T. Mattila; Luke O’Gorman; Galuh Astuti; Anna Tervasmäki; Susanna Koivuluoma; Tiina M. Mattila; Mervi Grip; Robert Winqvist; Outi Kuismin; Jukka Moilanen; Alexander Hoischen; Christian Gilissen; Tuomo Mantere; Katri Pylkäs
• Keywords: Exome; Human genetics; MLH1

Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They known to be causal underlie predisposition various diseases. However, the role CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis rare 98 high-risk Northern Finnish cases. After filtering, selected candidate alleles were validated characterized with combination orthogonal methods, including PCR-based approaches, optical genome mapping long-read sequencing. This revealed three recurrent alterations: 31 kb deletion co-occurring retrotransposon insertion (delins) RAD52 , 13.4 HSD17B14 64 partial duplication RAD51C . Notably, all these encode proteins involved pathways previously identified as essential for development. Variants genotyped geographically matched cases controls (altogether 278 hereditary 1983 unselected cases, 1229 controls). The delins both showed significant enrichment among indications disease susceptibility. was 7/278 (2.5%, P = 0.034, OR 2.86, 95% CI 1.10–7.45) 8/278 (2.9%, 0.014, 3.28, 1.31–8.23), frequency being 11/1229 (0.9%). suggests very rare, only 2/278 2/1229 (P 0.157, 4.45, 0.62–31.70). identification genes, especially relatively high alterations population, highlights importance studying alongside single nucleotide when searching factors underlying predisposition.