Long-read genome sequencing resolves complex structural variants in exome-negative developmental and epileptic encephalopathy

Long-read genome sequencing in 124 sporadic developmental and epileptic encephalopathy families resolved complex structural variants, enabling diagnoses in 21 families (16.9%).

• Why it matters: About two-thirds of DEE patients remain undiagnosed after exome sequencing, and difficult-to-resolve noncoding and complex structural variants likely contribute to this gap.
• What they did: The study performed trio long-read genome sequencing (Oxford Nanopore or PacBio HiFi), complemented by short-read genome sequencing and mRNA sequencing, then compared diagnostic yields across methods.
• The result: Long-read sequencing particularly enabled accurate characterization of Alu-mediated CDKL5 and STXBP1 deletions, a MEF2C deletion with large inversion, and a copy-neutral SCN1A inversion, with RNA sequencing confirming pathogenicity for multiple SVs.