The Phenotype & Genotype of Usher Syndrome in Ireland

Abstract

Purpose : Usher Syndrome (USH) is the most common syndromic retinitis pigmentsoa (RP) manifesting with dual sensory impairments (deafness, blindness). Three subtypes are described by timing, severity and progression of hearing loss and presence or absence of vestibular function. Fourteen genes have been implicated (USH1:9, USH2:3, USH3:2). Herein, we describe the first comprehensive phenotype & genotype analysis of USH in Ireland.

Methods : Irish patients with inherited retinal degenerations (IRDs) were invited to participate in the Irish national IRD population study (Target 5000). Thorough clinical assessment clarified the nature of visual, hearing and vestibular symptoms. USH subtype was determined by clinical and genetic characteristics. Genotype was assessed via a panel-based NGS approach of 256 IRD-implicated genes. Clinical and genetic features were analysed between the groups.

Results : Thirty-nine patients with an USH phenotype from 36 pedigrees were recruited. Mean age: 42.65y; 58.97% male. Overall prevalence of USH: 1.53:100 000. Subtype breakdown: USH1: 33%, USH2: 67%, no cases of USH3. Where possible, these outcomes were validated against genotype, a genetic diagnosis being confirmed in 89.7% of cases. Genotype was confirmed in 84.6% of USH1 (76.9% MYO7A) and 92.3% of USH2 (69.2% USH2A). Novel variants were detected including the largest USH1C homozygous deletion yet reported. Deafness was congenital in 61%, <5y in 33% and 6–10y in 6%. Vestibular imbalance was poorly reported. Mean visual acuity was 0.49(R) and 0.48(L) LogMAR. Cystoid macular oedema was present in 22% of eyes. Lens status: 33.3% pseudophakic, 41.6% non-visually significant posterior subcapsular cataract, and 25% no clinically detectable cataract.

Conclusions : The Irish diaspora has far-reaching influence on the genetic landscape of the western world. >10% of the American, Canadian, New Zealand, Australian and UK populations claim Irish heritage. Determining the genetic aetiology of inherited retinal degenerations in Ireland is highly relevant, both for Irish patients and global IRD statistics. Absence of USH3 in this cohort is consistent with data from the UK; clusters of USH3 exist in geographically isolated areas (e.g. rural Scandanavia). Usher Syndrome is a devastating diagnosis with dual sensory impairments, thus confirming genotype early on confers useful prognostic data and allows assessment of novel therapeutic avenues (e.g. MYO7A gene therapy).

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.