Ana Rita Lameiras1, Ana Cláudia Gonçalves2, Ricardo Santos1, Assunção O'Neill3, Luís Roque Dos Reis1, Tiago Daniel Matos4, Graça Fialho4, Helena Caria5, Pedro Escada1. 1. ENT-CHLO, HEM, ENT Service, Centro Hospitalar de Lisboa Ocidental EPE, Egas Moniz Hospital, Lisbon, Portugal; NMS/UNL, Department of Otorhinolaryngology, Nova Medical School, New University of Lisbon, Lisbon, Portugal. 2. BioISI - Biosystems & Integrative Sciences Institute, Faculty of Science of the University of Lisbon, Lisbon, Portugal. Electronic address: Claudiagoncalves030@gmail.com. 3. ENT-CHLO, HEM, ENT Service, Centro Hospitalar de Lisboa Ocidental EPE, Egas Moniz Hospital, Lisbon, Portugal; NMS/UNL, Department of Anatomy, Nova Medical School, New University of Lisbon, Lisbon, Portugal. 4. BioISI - Biosystems & Integrative Sciences Institute, Faculty of Science of the University of Lisbon, Lisbon, Portugal. 5. BioISI - Biosystems & Integrative Sciences Institute, Faculty of Science of the University of Lisbon, Lisbon, Portugal; ESS/IPS, School of Health, Polytechnic Institute of Setúbal, Setúbal, Portugal.
Abstract
INTRODUCTION: Recent advances in molecular genetics have increased the identification of genes and mutations responsible for inherited forms of hearing loss (HL), enabling early detection of these cases. Approximately, 60% of early-onset HL cases are due to genetic causes, of which 70% are non-syndromic. Of these, 75-80% are inherited in an autosomal recessive pattern (DFNB). Mutations in GJB2 gene, coding for connexin 26 (Cx26), are the major cause of autosomal recessive hereditary HL, but some GJB2 mutations are yet of unclear or controversial significance. OBJECTIVES: The aim of the present study was to identify the etiology of hearing loss, and correlate genotype-phenotype, in two Portuguese siblings with profound and moderate non-syndromic sensorineural bilateral HL. MATERIAL AND METHODS: The affected subjects and their parents underwent audiological and genetic study. Molecular analysis of GJB2 gene was performed, searching for mutations in the coding region and receptor splicing site by automated sequencing. RESULTS: The onset and the degree of HL were different in the two affected subjects. However, the same GJB2 genotype [p.Met34Thr]+[p.Arg184Pro] was identified in both siblings. The c.551G>C (p.Arg184Pro) and c.101T>C (p.Met34Thr) missense variants were inherited from the father and mother, respectively, both heterozygous carriers of these variants. CONCLUSION: The clinical and genetic data here presented suggest that the non-syndromic sensorineural HL of these two Portuguese siblings might be due to the presence of p.Met34Thr and p.Arg184Pro variants in compound heterozygosity. If so, p.Met34Thr variant could have function as a hypomorphic allele that may cause HL depending on the opposing GJB2 allele. The observed phenotypic variability may not, however, be solely explained by variable expression of this genotype. A putative modifier gene or mutations in another HL-associated gene could probably be contributing to the severe HL in one of the siblings.
INTRODUCTION: Recent advances in molecular genetics have increased the identification of genes and mutations responsible for inherited forms of hearing loss (HL), enabling early detection of these cases. Approximately, 60% of early-onset HL cases are due to genetic causes, of which 70% are non-syndromic. Of these, 75-80% are inherited in an autosomal recessive pattern (DFNB). Mutations in GJB2 gene, coding for connexin 26 (Cx26), are the major cause of autosomal recessive hereditary HL, but some GJB2 mutations are yet of unclear or controversial significance. OBJECTIVES: The aim of the present study was to identify the etiology of hearing loss, and correlate genotype-phenotype, in two Portuguese siblings with profound and moderate non-syndromic sensorineural bilateral HL. MATERIAL AND METHODS: The affected subjects and their parents underwent audiological and genetic study. Molecular analysis of GJB2 gene was performed, searching for mutations in the coding region and receptor splicing site by automated sequencing. RESULTS: The onset and the degree of HL were different in the two affected subjects. However, the same GJB2 genotype [p.Met34Thr]+[p.Arg184Pro] was identified in both siblings. The c.551G>C (p.Arg184Pro) and c.101T>C (p.Met34Thr) missense variants were inherited from the father and mother, respectively, both heterozygous carriers of these variants. CONCLUSION: The clinical and genetic data here presented suggest that the non-syndromic sensorineural HL of these two Portuguese siblings might be due to the presence of p.Met34Thr and p.Arg184Pro variants in compound heterozygosity. If so, p.Met34Thr variant could have function as a hypomorphic allele that may cause HL depending on the opposing GJB2 allele. The observed phenotypic variability may not, however, be solely explained by variable expression of this genotype. A putative modifier gene or mutations in another HL-associated gene could probably be contributing to the severe HL in one of the siblings.
Authors: Erna V Ivarsdottir; Hilma Holm; Stefania Benonisdottir; Thorhildur Olafsdottir; Gardar Sveinbjornsson; Gudmar Thorleifsson; Hannes P Eggertsson; Gisli H Halldorsson; Kristjan E Hjorleifsson; Pall Melsted; Arnaldur Gylfason; Gudny A Arnadottir; Asmundur Oddsson; Brynjar O Jensson; Aslaug Jonasdottir; Adalbjorg Jonasdottir; Thorhildur Juliusdottir; Lilja Stefansdottir; Vinicius Tragante; Bjarni V Halldorsson; Hannes Petersen; Gudmundur Thorgeirsson; Unnur Thorsteinsdottir; Patrick Sulem; Ingibjorg Hinriksdottir; Ingileif Jonsdottir; Daniel F Gudbjartsson; Kari Stefansson Journal: Commun Biol Date: 2021-06-09