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

Complex structural variants (Alu-mediated CDKL5 and STXBP1 deletions, MEF2C deletion with large inversion, SCN1A inversion, t(X;17) translocation disrupting CDKL5) and non-coding variants

One hundred and twenty-four families with sporadic developmental and epileptic encephalopathy, unsolved by exome sequencing, underwent trio long-read genome sequencing (Oxford Nanopore or PacBio HiFi), complemented where available by short-read genome sequencing and RNA sequencing of the index case. A diagnosis was established in 21 families (16.9%), 14 of whose variants were retrospectively detectable in the prior exome; two non-coding variants (SCN1A, RNU2-2) were detectable by both short-read and long-read genome sequencing. Five structural variants required genome sequencing: long-read sequencing characterized Alu-mediated CDKL5 and STXBP1 deletions and a MEF2C deletion with a large inversion, and resolved a balanced t(X;17) translocation disrupting CDKL5. RNA sequencing confirmed the pathogenicity of two structural variants and two CNVs, and ZNF569 and ZNF570 emerged as candidate epilepsy genes. This is a medRxiv preprint, not yet peer-reviewed.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A twofold and honest message: in exome-negative DEE, the gain from genome sequencing is modest, and two diagnoses out of three were already reachable by exome reanalysis, which puts systematic reanalysis ahead of any new technology. Long-read sequencing keeps a specific value for resolving complex, repeat-rich rearrangements that short-read sequencing detects without always characterizing. A preprint to reread once peer-reviewed, and ZNF569 and ZNF570 should be regarded as candidates until replicated.

Analysis by Dr Thibaut Benquey