Fabiana D'Esposito1,2,3,4, Viviana Randazzo3, Gilda Cennamo5, Nicola Centore2, Paolo Enrico Maltese6, Rita Malesci7, Luca D'Andrea2, Matteo Bertelli5,6, Elio Marciano7, Giuseppe de Crecchio2, Antonino Pioppo3,8, Adriano Magli9, Maria Francesca Cordeiro1. 1. Imperial College Ophthalmic Research Group (ICORG) Unit, Western Eye Hospital, Imperial College Healthcare NHS Trust, London, UK. 2. Eye Clinic, Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, Naples, Italy. 3. Centro di Ipovisione, U.O.C. di Oculistica A.O.O.R. Villa Sofia-Cervello, Palermo, Italy. 4. MAGI Euregio, Bolzano, Italy. 5. Eye Clinic, Department of Public Health, University of Naples Federico II, Naples, Italy. 6. MAGI'S Lab, Rovereto, Italy. 7. Unit of Audiology and Vestibology, University of Naples Federico II, Naples, Italy. 8. U.O.C. di Oculistica A.O.O.R Villa Sofia-Cervello, Palermo, Italy. 9. Department of Pediatric Ophthalmology, University of Salerno, Fisciano, Italy.
Abstract
PURPOSE: Usher syndrome (USH) is an autosomal recessive disorder characterized by congenital sensorineural hearing impairment and retinitis pigmentosa. Classification distinguishes three clinical types of which type I (USH1) is the most severe, with vestibular dysfunction as an added feature. To date, 15 genes and 3 loci have been identified with the USH1G gene being an uncommon cause of USH. We describe an atypical USH1G-related phenotype caused by a novel homozygous missense variation in a patient with profound hearing impairment and relatively mild retinitis pigmentosa, but no vestibular dysfunction. METHODS: A 26-year-old female patient with profound congenital sensorineural hearing loss, nyctalopia and retinitis pigmentosa was studied. Audiometric, vestibular and ophthalmologic examination was performed. A panel of 13 genes was tested by next-generation sequencing (NGS). RESULTS: While the hearing loss was confirmed to be profound, the vestibular function resulted normal. Although typical retinitis pigmentosa was present, the age at onset was unusually late for USH1 syndrome. A novel homozygous missense variation (c.1187T>A, p.Leu396Gln) in the USH1G gene has been identified as causing the disease in our patient. CONCLUSIONS: Genetic and phenotypic heterogeneity are very common in both isolated and syndromic retinal dystrophies and sensorineural hearing loss. Our findings widen the spectrum of USH allelic disorders and strength the concept that variants in genes that are classically known as underlying one specific clinical USH subtype might result in unexpected phenotypes.
PURPOSE: Usher syndrome (USH) is an autosomal recessive disorder characterized by congenital sensorineural hearing impairment and retinitis pigmentosa. Classification distinguishes three clinical types of which type I (USH1) is the most severe, with vestibular dysfunction as an added feature. To date, 15 genes and 3 loci have been identified with the USH1G gene being an uncommon cause of USH. We describe an atypical USH1G-related phenotype caused by a novel homozygous missense variation in a patient with profound hearing impairment and relatively mild retinitis pigmentosa, but no vestibular dysfunction. METHODS: A 26-year-old female patient with profound congenital sensorineural hearing loss, nyctalopia and retinitis pigmentosa was studied. Audiometric, vestibular and ophthalmologic examination was performed. A panel of 13 genes was tested by next-generation sequencing (NGS). RESULTS: While the hearing loss was confirmed to be profound, the vestibular function resulted normal. Although typical retinitis pigmentosa was present, the age at onset was unusually late for USH1 syndrome. A novel homozygous missense variation (c.1187T>A, p.Leu396Gln) in the USH1G gene has been identified as causing the disease in our patient. CONCLUSIONS: Genetic and phenotypic heterogeneity are very common in both isolated and syndromic retinal dystrophies and sensorineural hearing loss. Our findings widen the spectrum of USH allelic disorders and strength the concept that variants in genes that are classically known as underlying one specific clinical USH subtype might result in unexpected phenotypes.
Authors: Eric Nisenbaum; Torin P Thielhelm; Aida Nourbakhsh; Denise Yan; Susan H Blanton; Yilai Shu; Karl R Koehler; Aziz El-Amraoui; Zhengyi Chen; Byron L Lam; Xuezhong Liu Journal: Ear Hear Date: 2022 Jan/Feb Impact factor: 3.562