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

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

doi:10.1038/s10038-019-0706-1

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.

Highlights

Biallelic variants in HARS2 have been associated with Perrault syndrome, a rare autosomal recessive disease characterised by variable degrees of sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency (POI) in 46, XX karyotype
Biallelic variants in six causative genes have been associated with Perrault syndrome:HSD17B4 (MIM 233400) [7], HARS2 (MIM 614926) [3], LARS2 (MIM 615300) [8], CLPP (MIM 614129) [9], C10orf2 (MIM 616138) [10], and ERAL1 (MIM 607435) [6]
In each family the variant was in trans to a second putative pathogenic variant in HARS2

Summary

Introduction

HARS2 links histidine to its cognate tRNA in the mitochondrial matrix [1] and is an essential factor for mitochondrial translation [2]. Biallelic variants in HARS2 have been associated with Perrault syndrome, a rare autosomal recessive disease characterised by variable degrees of sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency (POI) in 46, XX karyotype females [3, 4]. Biallelic variants in six causative genes have been associated with Perrault syndrome:HSD17B4 (MIM 233400) [7], HARS2 (MIM 614926) [3], LARS2 (MIM 615300) [8], CLPP (MIM 614129) [9], C10orf (MIM 616138) [10], and ERAL1 (MIM 607435) [6]

Methods

Results

Conclusion