Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study. Issue 5 (21st March 2022)

• Record Type: Journal Article
• Authors: Hufnagel, Robert B.; Liang, Wendi; Duncan, Jacque L.; Brewer, Carmen C.; Audo, Isabelle; Ayala, Allison R.; Branham, Kari; Cheetham, Janet K.; Daiger, Stephen P.; Durham, Todd A.; Guan, Bin; Heon, Elise; Hoyng, Carel B.; Iannaccone, Alessandro; Kay, Christine N.; Michaelides, Michel; Pennesi, Mark E.; Singh, Mandeep S.; Ullah, Ehsan
• Is Part Of: Human mutation. Volume 43:Issue 5(2022)
• Page Start: 613
• Page End: 624
• Publication Date: 2022-03-21
• Subjects: genotype -- hearing loss -- photoreceptor degeneration -- retinitis pigmentosa -- USH2A -- Usher syndrome; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24365
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: We assessed genotype–phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) ( n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) ( n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose‐dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue‐specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes. Abstract : The variants/genotypes and their effects are independent of clinical diagnosis. For the retina, the yellow sign with an exclamation point indicates a nonsyndromic retinitis pigmentosa‐associated missense allele, with intermediate degeneration compared with the degeneration due to biallelic loss of function variation (stop sign). In the inner ear, the number of loss of function variants correlates with onset and severity of hearing loss.