Importance of phenotype in guiding re-interrogation of genetic results to achieve the correct molecular diagnosis in retinal disease

Abstract

Purpose : In many settings, patients with suspected genetic disease undergo whole genome sequencing (WGS) or multi-gene testing. In this study, we report cases where such testing failed initially to yield the cause, but careful phenotyping guided re-interrogation of the data to achieve the correct genetic diagnosis.

Methods : Clinical and genetic data were retrieved from cases within our service where initial testing was negative or pointed to a gene inconsistent with the phenotype. Clinical features, including findings on imaging and electrophysiology, guided re-analysis of the genetic results.

Results : The first case was an 18 year old male with high myopia, subnormal vision, and poor night vision since a young age. The son of his maternal aunt was similarly affected. WGS was reported negative. Full-field electroretinograms (ERGs) suggested incomplete congenital stationary night blindness. This, together with a family history suggesting X-linked inheritance, implicated CACNA1F. Re-examination of data from this gene revealed a frame-shifting variant that had failed the filtering pipeline. The second case was a 42 year old man with bilateral sequential visual loss occurring 11 years previously. Testing for the 3 common Leber Hereditary Optic Neuropathy (LHON) variants was negative. WGS yielded two variants in EYS, a gene associated with autosomal recessive retinitis pigmentosa (RP). Normal ultra-widefield autofluorescence and ERGs excluded RP. Reanalysis of WGS data for DNAJC30 (a gene recently associated with a phenocopy of LHON) revealed homozygosity for a pathogenic variant. The third case was a 50 year old man previously diagnosed with central serous retinopathy, but later suspected to have a vitelliform maculopathy (though unilateral). Testing of a panel of macular dystrophy genes was reported negative. Previous angle closure and electrophysiology findings (normal ERGs; abolished electrooculogram light rise), suggested Best disease was likely. Reanalysis of genetic data revealed a BEST1 variant that had been designated of uncertain significance, but which, in another transcript, corresponded to a known pathogenic variant.

Conclusions : Careful phenotypic characterisation, even in the era of WGS, can guide which genes to re-interrogate and exclude genes implicated in apparently positive reports. The importance of close multi-disciplinary work is highlighted.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.