Optical Genome Mapping for the Identification of Complex Structural Variants in Hereditary Angioedema.

PURPOSE: Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is caused by heterozygous pathogenic variants in the SERPING1 gene. Structural variants (SVs) account for 10–15% of cases, and while many can be identified using conventional diagnostic approaches such as multiplex ligation-dependent probe amplification (MLPA), some remain difficult to detect. This study aims to assess the utility of optical genome mapping (OGM) for the detection of both typically described and atypical structural variants in HAE-C1INH. METHODS: MLPA, OGM, long-read whole-genome sequencing (LR-WGS), Sanger sequencing and cDNA analysis. RESULTS: First, we assessed whether OGM could detect common SVs in HAE-C1INH affecting the SERPING1 coding region. We tested a family previously diagnosed by MLPA with a large heterozygous deletion encompassing exons 1–2 of SERPING1. OGM successfully identified this deletion in both affected members. Next, we analyzed a three-generation HAE-C1INH family with no genetic findings after Sanger sequencing and MLPA. OGM revealed a 3.8 kb insertion in SERPING1, which was further characterized using LR-WGS as a SINE-VNTR-Alu (SVA) mobile element inserted in intron 7, demonstrating the complementary role of LR-WGS in precisely defining the nature and location of SVs detected by OGM. Finally, we demonstrated that the allele carrying the SVA insertion was absent in cDNA resulting in SERPING1 functional haploinsufficiency in this family. CONCLUSION: OGM is a reliable and robust technique for detecting SVs affecting both coding and non-coding regions in HAE-C1INH. Using OGM, we report the first case of HAE-C1INH caused by the insertion of an SVA mobile element.