Genetic dissection of structural variants in study subjects with antithrombin deficiency by nanopore sequencing

Abstract

The characterisation of structural variants (SVs) is challenging. In antithrombin deficiency (ATD), MLPA detects SVs in >8% of cases but does not characterise the SV. We run long-range PCR, NGS, CGH array, and/or nanopore sequencing in 35 study subjects with SVs detected by MLPA, showing the limitations and strengths of these methods. Nanopore sequencing identified all SVs independently of size or type, resolved conflictive results, identified the first complex SV involved in this disorder, and determined the mechanism involved in all these SVs. Moreover, nanopore sequencing also detected a retrotransposon insertion in two cases with ATD and unknown molecular base. Our study underscores the utility of nanopore sequencing to identify and fully characterise SVs.