Complex de novo structural variants are an underestimated cause of rare disorders

Abstract

Complex de novo structural variants (dnSVs) are crucial genetic factors in rare disorders, yet their prevalence and characteristics in rare disorders remain poorly understood. Here, we conducted a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, as part of the UK 100,000 Genomes Project. We identified 1,872 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n=158; 8.4%) emerged as the third most common type of SV, following simple deletions and duplications. We classified 65% of these complex dnSVs into 11 subtypes, based on the classification established through the analysis of cancer whole genomes. 1.4% of probands with neurodevelopmental disorders harbour at least one complex dnSV, a rate two times higher than previously reported. Intriguingly, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or exome-seq methods were found to be complex dnSVs. This study highlights the importance of complex dnSVs in rare disorders and demonstrates the necessity of careful genomic analysis to avoid overlooking these variants.