NCM 2022: Long-read sequencing resolves cryptic structural variation in individuals with syndromic intellectual disability

A genetic diagnosis in intellectual disability (ID) is crucial for further disease management yet is currently lacking in 40% of patients. This can be partly explained by missed structural variants (SVs), which are large genomic rearrangements that are hard to discover through conventional methods. We applied nanopore long-read sequencing onto 13 proband-parent trios with unexplained ID, and three single proband cases to identify, or further specify, cryptic (de novo) SVs. We found approximately 21,700 SVs per individual and zero to one de novo variants per proband in a trio setting. Five de novo events and single case variants were further unravelled, revealing more complex rearrangements in three out of five cases. Oxford Nanopore long-read sequencing can uncover significantly more variants compared with short-read sequencing, as well as pinpoint exact breakpoints and reveal complex rearrangements and de novo variants. This study highlights the potential of nanopore long-read sequencing as a standard molecular method for SV identification.