Diagnostic discovery of structural variants causing foveal hypoplasia using SVRare and long-read nanopore sequencing.

Structural variant detection with the SVRare tool and long-read nanopore sequencing in foveal hypoplasia cases unsolved by exome sequencing.

Re-analysis of ten exome-unsolved foveal hypoplasia cases using SVRare, a tool integrating Canvas and Manta outputs to prioritise plausible structural variants (SVs); two cases were solved. Extended to the 100,000 Genomes Project, the approach identified pathogenic SVs in 11 further cases. In total, 11 SVs in five genes (SLC38A8, PAX6, OCA2, GPR143, CACNA1F) explained disease in 13 patients. The analysis also recovered an apparently novel OCA2 deletion that in fact corresponds to the known African founder variant of oculocutaneous albinism.

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

Another illustration that structural variants are a reservoir of diagnoses missed by exome sequencing, here in developmental ophthalmology. The anecdote of the 'novel' OCA2 deletion turning out to be a known founder variant is a salutary reminder of the pitfalls of SV interpretation and reporting. A tool and approach transferable to other indications with high SV suspicion.

Analysis by Dr Thibaut Benquey