USH2A – Retinitis Pigmentosa

USH2A encodes the basement‐membrane protein usherin, and biallelic variants cause autosomal recessive retinitis pigmentosa (RP) (MONDO_0019200). The gene–disease association is Definitive. Hundreds of unrelated probands with USH2A‐associated RP have been described, with segregation in multiple families and concordant functional studies supporting a causal role (gene_disease_association score).

1 Clinical Validity

Autosomal recessive inheritance is established for USH2A‐related RP. Over 23 independent families with cosegregation of biallelic USH2A variants and RP have been reported (PMID:10775529). Large cohorts in Chinese (n=1381; 15.8% USH2A‐positive) and Spanish (n=224; 4.5% Cys759Phe) populations further reinforce recurrence of pathogenic alleles (PMID:32188678, PMID:10775529). Comprehensive segregation analyses and support from multiple unrelated pedigrees justify a Definitive classification.

2 Genetic Evidence

RP due to USH2A shows autosomal recessive inheritance, with compound heterozygous or homozygous loss‐of‐function and missense variants. Over 1 000 probands across case series have been molecularly diagnosed, reaching the genetic evidence cap for a Strong molecular tier; families display segregation of biallelic USH2A variants with RP phenotype (PMID:20309401, PMID:24227914). The most frequent variant c.2276G>T (p.Cys759Phe) occurs in diverse populations, while c.2802T>G (p.Cys934Trp) is enriched in East Asians.

3 Functional / Experimental Evidence

In vitro and in vivo assays demonstrate that USH2A variants perturb usherin function. Minigene splicing assays show aberrant exon inclusion for deep-intronic and noncanonical splice‐site alleles (PMID:36362125). Patient‐derived retinal organoids and iPSC models recapitulate photoreceptor layer disorganization and reduced laminin expression (PMID:31481876). Zebrafish knock-in of c.7595-2144A>G confirms mis‐splicing and photoreceptor dysfunction. These data support a Moderate functional evidence tier.

4 Conflicting Evidence

The pathogenicity of homozygous p.Cys759Phe was questioned after its identification in healthy siblings; targeted resequencing revealed an alternative PDE6B mutation as causal (PMID:25823529). However, extensive reanalysis and zebrafish modeling revalidated p.Cys759Phe as deleterious, resolving earlier uncertainty.

5 Conclusion & Clinical Utility

Definitive evidence links biallelic USH2A variants to autosomal recessive RP. Genetic testing of USH2A enables molecular diagnosis in ~15% of RP cases, informs prognosis (variant‐specific severity), and guides genetic counseling. Functional assays pave the way for personalized therapies (antisense‐mediated exon skipping and CRISPR correction). Key Take-home: USH2A testing is essential for RP diagnosis, patient management, and future therapeutics.

References

• Am. J. Hum. Genet. • 2000 • Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss PMID:10775529
• Mol. Vis. • 2010 • Novel USH2A compound heterozygous mutations cause RP/USH2 in a Chinese family PMID:20309401
• Mol. Vis. • 2013 • Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa PMID:24227914
• Front. Cell. Neurosci. • 2019 • Modeling Retinitis Pigmentosa: Retinal Organoids Generated From the iPSCs of a Patient With the USH2A Mutation Show Early Developmental Abnormalities PMID:31481876
• PLoS One • 2018 • Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families PMID:29912909
• Am. J. Med. Genet. A • 2015 • Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F PMID:25823529

Evidence Based Scoring (AI generated)