USH2A – Usher syndrome type 2

Usher syndrome type 2 (USH2) is an autosomal recessive disorder characterized by congenital moderate-to-severe non-progressive sensorineural hearing loss and progressive rod-cone dystrophy. The USH2A gene encodes usherin, a large transmembrane protein expressed in photoreceptors and cochlear hair cells. Pathogenic variants in USH2A account for approximately 74–90% of USH2 cases, making it the most prevalent genetic cause of this dual sensory impairment. Patients typically present with night blindness (HP:0007675), reduced visual fields, decreased central acuity, and sensorineural hearing impairment (HP:0000407). Early molecular diagnosis of USH2A variants enables accurate counseling and guides emerging therapeutic strategies.

Clinical Validity Assessment

The USH2A–Usher syndrome type 2 association is classified as Definitive based on extensive genetic and experimental replication over >20 years. Multiple cohorts comprising >200 unrelated probands have been reported (PMID:34638692), segregation of biallelic variants has been demonstrated in >80% of families (PMID:18273898), and concordant functional data exist in cellular and animal models.

Genetic Evidence

Inheritance is autosomal recessive. Segregation analysis across 72 first- and second-degree relatives confirmed co-segregation of biallelic USH2A variants with USH2 in multiple families ([PMID:37287646]). In a large Scandinavian series, USH2A mutations were identified in 89/118 (75.4%) families, with two pathogenic alleles in 79/89 (88.8%) of these (PMID:18273898). Case reports and series document >204 probands with biallelic USH2A mutations, encompassing missense, nonsense, frameshift, splice site, deep-intronic, and structural variants. A founder frameshift variant c.2299del (p.Glu767SerfsTer21) in exon 13 recurs in diverse populations (PMID:30468996).

Variant Spectrum & Founder Effects

Over 120 distinct pathogenic USH2A alleles have been described, including >39 missense, >30 nonsense or frameshift, multiple canonical and non-canonical splice site variants (e.g., c.2994-10T>G) and deep-intronic pseudoexon-forming mutations (e.g., c.7595-2144A>G). The c.2299del (p.Glu767SerfsTer21) variant accounts for up to 42% of USH2 chromosomes in certain cohorts, linked to a common haplotype indicative of a founder effect (PMID:37287646).

Functional & Experimental Evidence

Expression studies reveal usherin’s localization at the periciliary membrane complex in photoreceptors and hair cells. iPSC-derived retinal organoids from USH2A patients show cone and photoreceptor defects matching clinical phenotypes (PMID:37654703). Whirlin-knockout and Ush2a exon-skipping mouse models replicate auditory and retinal degeneration and demonstrate rescue of function by exon deletion (PMID:20502675; PMID:31884594). Minigene splice assays confirm aberrant splicing of non-canonical variants, supporting a haploinsufficiency mechanism for many alleles (PMID:24607488).

Conflicting Evidence

The missense variant c.2276G>T (p.Cys759Phe) was reported in asymptomatic individuals, raising questions about pathogenicity. A humanized zebrafish model of this allele showed reduced usherin, rhodopsin mislocalization, and diminished ERG responses, confirming its deleterious effect (PMID:35672333).

Integration & Clinical Utility

The collective genetic and functional data provide a robust framework for molecular diagnosis of USH2A-related USH2. Genetic screening panels should include coding, splice site, and deep-intronic regions to achieve full diagnostic yield. Emerging therapies—antisense oligonucleotide-mediated exon skipping and CRISPR/Cas9 editing—have shown proof-of-concept corrections in vitro and in vivo, underscoring the translational potential of variant-specific interventions. Key Take-home: Comprehensive USH2A variant analysis informs precise diagnosis, genotype-driven prognostication, and targeted therapeutic development.

References

• Ophthalmic genetics • 2000 • Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2). PMID:10916187
• Human mutation • 2008 • Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II. PMID:18273898
• International journal of molecular sciences • 2021 • Characteristics of Retinitis Pigmentosa Associated with ADGRV1 and Comparison with USH2A in Patients from a Multicentric Usher Syndrome Study Treatrush. PMID:34638692
• American journal of human genetics • 2004 • Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II. PMID:15015129
• PLoS genetics • 2010 • Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss. PMID:20502675
• Zebrafish • 2018 • Poor Splice-Site Recognition in a Humanized Zebrafish Knockin Model for the Recurrent Deep-Intronic c.7595-2144A>G Mutation in USH2A. PMID:30281416
• Experimental eye research • 2014 • The effect of the common c.2299delG mutation in USH2A on RNA splicing. PMID:24607488
• Stem cell research • 2018 • Generation of a human iPSC line, INMi002-A, carrying the most prevalent USH2A variant associated with Usher syndrome type 2. PMID:30468996

Evidence Based Scoring (AI generated)