POLD3 haploinsufficiency is linked to non-syndromic sensorineural adult-onset progressive hearing and balance impairments.

Autor: Chouery E; Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon. eliane.choueiry01@lau.edu.lb., Mehawej C; Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon., Saade R; Department of Otolaryngology-Head and Neck Surgery, Lebanese American University, Byblos, Lebanon., Barake R; Department of Otolaryngology-Head and Neck Surgery, Lebanese American University, Byblos, Lebanon., Zarecki P; School of Biosciences, University of Sheffield, Sheffield, UK., Gennery C; School of Biosciences, University of Sheffield, Sheffield, UK., Corbani S; Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon., Korban R; Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon., Hamam A; Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon., Nasser Eldin J; Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon., Yamout M; Yamout hearing center, Beirut, Lebanon., Banna M; Yamout hearing center, Beirut, Lebanon., Yamout AKA; Yamout hearing center, Beirut, Lebanon., Adhami F; Adhami Advanced Audiology Center, Tripoli, Lebanon., Megarbane A; Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon. andre.megarbane@lau.edu.lb.; Institut Jérôme Lejeune, Paris, France. andre.megarbane@lau.edu.lb., Mustapha M; School of Biosciences, University of Sheffield, Sheffield, UK.; Neuroscience Institute, University of Sheffield, Sheffield, UK.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Oct 16. Date of Electronic Publication: 2024 Oct 16.
DOI: 10.1038/s41431-024-01715-7
Abstrakt: Hearing impairment (HI) is a significant health concern globally, influenced by genetic and environmental factors. We had identified a homozygous pathogenic variant in POLD3 in a Lebanese patient with an autosomal congenital recessive syndromic hearing loss (MIM#620869). This variant was found at heterozygous state in the parents, who developed progressive hearing impairment around age 40. We conducted a thorough clinical and genetic assessment of sixteen family members, including physical exams, audiometry and vestibular function evaluations. Additionally, gene expression analysis of the Pold3 gene was performed in mice using RNAscope. Twelve individuals were heterozygous for the variant in POLD3, of whom eight showed bilateral adult-onset HI, typically starting around ages 40-50, and two older patients displaying unilateral vestibular weakness. Additionally, two carriers of the variant developed cancer at an early age. RNAscope confirmed Pold3 expression in auditory and vestibular neurons. Exome sequencing analysis excluded the presence of pathogenic variants in any known hearing impairment or cancer predisposition genes. We present herein, for the first time, evidence of a heterozygous pathogenic POLD3 variant associated with a novel form of autosomal dominant progressive adult-onset hearing and vestibular impairments. We also highlight the necessity for further exploration of the role of POLD3 in cancer predisposition.
(© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)
Databáze: MEDLINE
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