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Tissue-specific genotype-phenotype correlations among USH2A-related disorders in the RUSH2A study

Hufnagel, Robert B; Liang, Wendi; Duncan, Jacque L; Brewer, Carmen C; Audo, Isabelle; Ayala, Allison R; Branham, Kari; ... Foundation Fighting Blindness Consortium Investigator Group; + view all (2022) Tissue-specific genotype-phenotype correlations among USH2A-related disorders in the RUSH2A study. Human Mutation , 43 (5) pp. 613-624. 10.1002/humu.24365.

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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.

Type: Article
Title: Tissue-specific genotype-phenotype correlations among USH2A-related disorders in the RUSH2A study
Location: United States
DOI: 10.1002/humu.24365
Publisher version: https://doi.org/10.1002/humu.24365
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: USH2A, Usher syndrome, genotype, hearing loss, photoreceptor degeneration, retinitis pigmentosa
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10147384
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