@article{a33d682fea72420a9dbaf0c3f4d641d1,
title = "Tissue-specific genotype–phenotype correlations among USH2A-related disorders in the RUSH2A study",
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.",
keywords = "USH2A, Usher syndrome, genotype, hearing loss, photoreceptor degeneration, retinitis pigmentosa",
author = "{for the Foundation Fighting Blindness Consortium Investigator Group} and Hufnagel, {Robert B.} and Wendi Liang and Duncan, {Jacque L.} and Brewer, {Carmen C.} and Isabelle Audo and Ayala, {Allison R.} and Kari Branham and Cheetham, {Janet K.} and Daiger, {Stephen P.} and Durham, {Todd A.} and Bin Guan and Elise Heon and Hoyng, {Carel B.} and Alessandro Iannaccone and Kay, {Christine N.} and Michel Michaelides and Pennesi, {Mark E.} and Singh, {Mandeep S.} and Ehsan Ullah",
note = "Funding Information: J. Duncan is a consultant for ConeSight Theraputics, DTx Pharma, Inc., Editas Theraputics, Eyevensys Theraputics, Nacuity, PYC Therapeutics, Spark Therapeutics, and Vedere Bio, Astellas; she receives financial support for clinical trials from Acucela, Abbvie/Allergan, AGTC Theraputics, Biogen/Nightstarx Theraputics, Inc., ProQR Therapeutics, Second Sight Medical Products, Inc and Neurotech USA, Inc.,;and she serves as a clinical advisory board member for SparingVision, Gyroscope Therapeutics, AGTC Therapeutics, Spark Therapeutics, ProQR Therapeutics, Nacuity, RD fund, and Foundation Fighting Blindness; Spouse: stock in RxSight. E. Heon is consultant for Novartis, Janssen, Deep Genomics. M. Singh is a consultant/advisor for Novartis, Janssen, Bayer, ReVision Therapeutics, and Acucela. M. Michaelides is supported by a grant from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. S. Daiger is on the Scientific Advisory Board for AGTC, Inc., a consultant to Spark Therapeutics and 4D Molecular Therapeutics (4DMT), and Jaeb Center for Research (genetics consulting); and receives grants from Foundation Fighting Blindness. K. Branham is a consultant/advisor for ProQR, Biogen, and Janssen. I. Audo is a consultant/advisor for Novartis, Sparing Vision, Janssen, Roche. C. Kay is a consultant for AGTC, Spark Therapeutics, Novartis, Astena Therapeutics; and receives clinical trial funding/investigator for AGTC, Foundation Fighting Blindness, Alkeus, Gyroscope, Regenx Bio, Nightstar Therapeutics/Biogen, Iveric Bio, ProQR Therapeutics, MeiraGTx/Janssen, and Kodiak; and receives equity from Astena Therapeutics. A. Iannaccone is a consultant for ClearView Healthcare Partners, Teladoc Health, GLG Group, Guidepoint, Astellas Institute for Regenerative Medicine, Roivant Pharma, Editas, Rhythm Pharmaceuticals, IQVIA, Gyroscope, Ocugen, and is a board member for Alia Therapeutics, and receives financial support from AGTC, Allergan, Acucela, ProQR, Retinagenix, 4D Molecular Therapeutics, BridgeBio Pharma/Retinagenix. C. Brewer receives support for this manuscript from NIDCD intramural research funds to Carmen Brewer for audiology support – budget number DC000064. J. Cheetham receives support for the manuscript from the Foundation Fighting Blindness, receives consulting fees from DTx Pharma and has stock in Abbvie. M. Pennesi receives consulting fees from 4D Molecular Therapeutics, Adverum, AGTC, Astellas Pharmaceuticals, Astena, Bayer, Biogen, Blue Rock, DTx, Editas, Endogena, Eyevensys, Horama, IVERIC, Nayan, Nacuity Pharmaceuticals, Novartis, Ocugen, Ora, ProQR, PYC Therapeutics, RegenexBio, Roche, Sanofi, Sparing Vision, Viewpoint Therapeutics, Verede; serves on a data safety monitoring board or advisory board for Akous and Gensight; and serves as a leadership or fiduciary role on AGTC (clinical trial support), Astena (equity, clinical advisory board), Biogen (clinical trial support), DTx (equity, scientific advisory board), Editas (clinical trial support), Endogena (scientific advisory board), Eyevensys (scientific advisory board), FFB (clinical trial support), Horama (scientific advisory board), Nayan (scientific advisory board), Nacutiy Pharmaceuticals (equity, scientific advisory board), Ocugen (equity, scientific advisory board), ProQR (clinical trials support), Sanofi (clinical trials support), Sparing Vision (clinical advisory board), Vedere (scientific advisory board) Funding Information: People – Eric Feng, National Eye Institute, Bethesda, MD. Robert B. Hufnagel – National Eye Institute Intramural Funds, ZIAEY000564, ZIAEY000565. Jacque L. Duncan – Research to Prevent: (unrestricted grant to UCSF), NIH‐NEI P30 EY002162 ‐ Core Grant for Vision (UCSF). Elise Heon – Fighting Blindness Canada, Henry Brent Chair in Innovative Pediatric Ophthalmology Research, Brendan Eye Research Fund. Mandeep S. Singh – Foundation Fighting Blindness Career Development Award, Joseph Albert Hekimian Fund. Janet K. Cheetham – Foundation Fighting Blindness (consulting). Carmen C. Brewer ‐‐ Intramural Research Program, National Institute on Deafness and Other Communication Disorders, ZDC000064. Isabelle Audo – Member of ERN‐EYE (European Reference Network for Rare Eye Diseases). Funded by Foundation Fighting Blindness. Funding Information: People ? Eric Feng, National Eye Institute, Bethesda, MD. Robert B. Hufnagel ? National Eye Institute Intramural Funds, ZIAEY000564, ZIAEY000565. Jacque L. Duncan ? Research to Prevent: (unrestricted grant to UCSF), NIH-NEI P30 EY002162 - Core Grant for Vision (UCSF). Elise Heon ? Fighting Blindness Canada, Henry Brent Chair in Innovative Pediatric Ophthalmology Research, Brendan Eye Research Fund. Mandeep S. Singh ? Foundation Fighting Blindness Career Development Award, Joseph Albert Hekimian Fund. Janet K. Cheetham ? Foundation Fighting Blindness (consulting). Carmen C. Brewer -- Intramural Research Program, National Institute on Deafness and Other Communication Disorders, ZDC000064. Isabelle Audo ? Member of ERN-EYE (European Reference Network for Rare Eye Diseases). Funded by Foundation Fighting Blindness. Publisher Copyright: {\textcopyright} 2022 Wiley Periodicals LLC.",
year = "2022",
month = may,
doi = "10.1002/humu.24365",
language = "English (US)",
volume = "43",
pages = "613--624",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "5",
}