Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review

Abstract

Purpose: Usher syndrome (USH) is a genetically heterogeneous group of autosomal recessive (AR) syndromic inherited retinal degenerations (IRDs) representing 50% of deaf-blindness. All subtypes include retinitis pigmentosa, sensorineural hearing loss, and vestibular abnormalities. Thorough phenotyping may facilitate genetic diagnosis and intervention. Here we report the clinical/genetic features of an Irish USH cohort.

Methods: USH patients were selected from the Irish IRD registry (Target 5000). Patients were examined clinically (deep-phenotyping) and genetically using a 254 IRD-associated gene target capture sequencing panel, USH2A exon, and whole genome sequencing.

Results: The study identified 145 patients (24.1% USH1 [n = 35], 73.8% USH2 [n = 107], 1.4% USH3 [n = 2], and 0.7% USH4 [n = 1]). A genetic diagnosis was reached in 82.1%, the majority (80.7%) being MYO7A or USH2A genotypes. Mean visual acuity and visual field (VF) were 0.47 ± 0.58 LogMAR and 31.3° ± 32.8°, respectively, at a mean age of 43 years. Legal blindness criteria were met in 40.7%. Cataract was present in 77.4%. ADGRV1 genotypes had the most VF loss, whereas USH2A patients had greater myopia and CDH23 had the most astigmatism. Variants absent from gnomAD non-Finnish Europeans and ClinVar represented more than 20% of the variants identified and were detected in ADGRV1, ARSG, CDH23, MYO7A, and USH2A.

Conclusions: USH is a genetically diverse group of AR IRDs that have a profound impact on affected individuals and their families. The prevalence and phenotype/genotype characteristics of USH in Ireland have, as yet, gone unreported. Understanding the genotype of Irish USH patients may guide clinical and genetic characterization facilitating access to existing/novel therapeutics.

Figure 1.

USH subtypes and candidate causative genotype. Candidate genotypes are displayed by clinical USH subtype columns with the largest contributions being MYO7A and USH2A.

Figure 2.

Mutation types for candidate causative USH genotypes. The majority of USH-associated variants are missense, frameshift and nonsense with a small contribution from splice-altering, structural and copy number variants. CNV, copy number variation.

Figure 3.

( A ) Boxplot contrasting VA for USH2A and MYOYA genotypes demonstrating worsening median VA with age, more notably with MYO7A. Number of eyes with recorded VA per genotype for each age range is numerically displayed at the top of the table above each bar. (B) Proportion of eyes by decade age ranges with VA ≥1.0 LogMAR (i.e., legal blindness) for USH2A and MYO7A genotypes. (C) Proportion of eyes by decade age ranges with VA ≤0.3 LogMAR for USH2A and MYO7A genotypes.

Figure 4.

(A) VA box plots for ADGRV1, CDH23, MYO7A, and USH2A genotypes. (B) VF (diameter) box plots for ADGRV1, CDH23, MYO7A, and USH2A genotypes. (C) VA box plots by variant type for USH2A. (D) VF (diameter) box plots by variant type for USH2A. (E) VA box plots by variant type for MYO7A. (F) VF (diameter) box plots by variant type for MYO7A.