A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families

Leigh A M Demain; Erica H Gerkes; Richard J H Smith; Leslie P Molina-Ramirez; Raymond T O'Keefe; William G Newman

doi:10.1038/s10038-019-0706-1

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A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families

Journal article

Open access

Peer reviewed

A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families

Leigh A M Demain, Erica H Gerkes, Richard J H Smith, Leslie P Molina-Ramirez, Raymond T O'Keefe and William G Newman

Journal of human genetics, Vol.65(3), pp.305-311

03/2020

DOI: 10.1038/s10038-019-0706-1

PMCID: PMC7500128

PMID: 31827252

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Abstract

HARS2 encodes mitochondrial histidyl-tRNA synthetase (HARS2), which links histidine to its cognate tRNA in the mitochondrial matrix. Biallelic variants in HARS2 are associated with Perrault syndrome, a rare recessive condition characterized by sensorineural hearing loss in both sexes and primary ovarian insufficiency in 46,XX females. Some individuals with Perrault syndrome have a broader phenotypic spectrum with neurological features, including ataxia and peripheral neuropathy. Here, we report a recurrent variant in HARS2 in association with sensorineural hearing loss. In affected individuals from three unrelated families, the variant HARS2 c.1439G>A p.(Arg480His) is present as a heterozygous variant in trans to a putative pathogenic variant. The low prevalence of the allele HARS2 c.1439G>A p.(Arg480His) in the general population and its presence in three families with hearing loss, confirm the pathogenicity of this variant and illustrate the presentation of Perrault syndrome as nonsyndromic hearing loss in males and prepubertal females.

Alleles

Amino Acyl-tRNA Synthetases - genetics

Child

Child, Preschool

Exome - genetics

Female

Genetic Predisposition to Disease

Gonadal Dysgenesis, 46,XX - genetics

Gonadal Dysgenesis, 46,XX - physiopathology

Hearing Loss, Sensorineural - genetics

Hearing Loss, Sensorineural - physiopathology

Heterozygote

Histidine-tRNA Ligase - genetics

Homozygote

Humans

Infant

Male

Mitochondria - genetics

Mutation, Missense - genetics

Pedigree

Primary Ovarian Insufficiency - genetics

Primary Ovarian Insufficiency - physiopathology

Details

Title: Subtitle: A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families
Creators: Leigh A M Demain - University of Manchester
Erica H Gerkes - University Medical Center Groningen
Richard J H Smith - University of Iowa
Leslie P Molina-Ramirez - University of Manchester
Raymond T O'Keefe - University of Manchester
William G Newman - University of Manchester
Resource Type: Journal article
Publication Details: Journal of human genetics, Vol.65(3), pp.305-311
DOI: 10.1038/s10038-019-0706-1
PMID: 31827252
PMCID: PMC7500128
NLM abbreviation: J Hum Genet
ISSN: 1434-5161
eISSN: 1435-232X
Grant note: R01 DC012049 / NIDCD NIH HHS
Language: English
Date published: 03/2020
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984256932602771

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