Abstract
BackgroundStudies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation.MethodsWe performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case.ResultsWe identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements.ConclusionsOur results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.
Highlights
Studies have shown that complex structural variants contribute to human genomic variation and can cause Mendelian disease
A duplication-triplication-inversion-duplication was found at the MECP2 and PLP1 loci in individuals with MECP2 duplication syndrome or Lubs syndrome (MIM: 300260) and Pelizaeus-Merzbacher disease (MIM: 312080) [5, 6], and a duplication-inversion-terminal deletion of chromosome 13 was present in foetuses with 13q deletion syndrome [7], among others [8,9,10]
A large Complex structural variant (cxSV) was identified on chromosome 6, comprising a 3.3 Mb duplication, two inversions of 4.9 Kb and 3.3 Mb, and a 16.3 Mb deletion (Fig. 1a; Table 1)
Summary
Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. Structural variants (SVs) are a major source of variation in the human genome and collectively account for more differences between individuals than single nucleotide variants (SNVs) [1, 2]. More complex rearrangements are typically composed of three or more breakpoint junctions and cannot be characterised as a single canonical SV type. These are known as non-canonical or complex SVs (cxSVs) [3, 4]. Extreme cases of cxSVs, such as chromothripsis, have been identified in both cancer cells and the germline and involve hundreds of rearrangements often concerning more than one chromosome [11, 15]
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