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

Abstract

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 conduct a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, obtained as part of the UK 100,000 Genomes Project. We identify 1,870 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n = 158; 8.4%) emerge as the third most common type of SV, following simple deletions and duplications. We classify 65% of these complex dnSVs into 11 subtypes. Among probands with dnSVs (n = 1,696), 9% exhibit exon-disrupting pathogenic dnSVs associated with the probands’ phenotype. Notably, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or whole-exome sequencing methods are found to be complex dnSVs. We also find distinct genomic properties of de novo deletions depending on the parent of origin. This study highlights the importance of complex dnSVs in the cause of rare disorders and demonstrates the necessity of specific genomic analysis to avoid overlooking these variants.