Analysis of familial exudative vitreoretinopathy (FEVR) cases in the UK 100 000 genomes project increases diagnostic rate and implicates heterozygous CTNND1 mutations in FEVR

Background Familial exudative vitreoretinopathy (FEVR) is an inherited eye disease characterised by the incomplete development of the retinal vasculature. Over 10 genes have been associated with FEVR, but there are still a substantial number of genetically unsolved cases. The aim of this study was to analyse whole genome sequencing (WGS) data from the FEVR cases in the Genomics England (GEL) 100 000 genomes project to identify the causative variants.

Methods WGS was performed by GEL and accessed within the GEL Research Environment. FEVR cases were identified using LabKey and candidate variants were extracted using the ‘gene-variant workflow’ and ‘CNV/SV workflow’ and by using BCFtools in unfiltered VCF files.

Results Fifty-nine FEVR probands were submitted to GEL. We found six novel and eight previously reported pathogenic variants in six genes known to underlie FEVR (TSPAN12, LRP5, FZD4, CTNNB1, KIF11 and NDP), as well as structural variants in TSPAN12 and KIF11. These accounted for 15/59 (25.4%) of FEVR cases. We also found candidate heterozygous variants in CTNND1 in three unsolved FEVR cases. Expanding the list of genes examined to include all genes reported to be mutated in ocular disorders likely solved a further four cases, indicating that these individuals may be misclassified as FEVR in GEL.

Conclusion By performing bespoke reanalysis of the FEVR GEL cohort, this study has highlighted additional heterozygous variants in CTNND1 in FEVR cases and increased the diagnostic yield from 20% solved by the GEL analysis pipeline to 37% (22/59), but the majority of FEVR cases remain without a molecular diagnosis.