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

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.

A Rare Case of Perrault Syndrome with Auditory Neuropathy Spectrum Disorder: Cochlear Implantation Treatment and Literature Review

“…Some authors have reported cases with an early onset acquired hearing loss that passes the newborn hearing screening [19]. In many cases, the audiometric curves are described to be upsloping [5,8,21] or flat [8,18,19,21,22]. One month after surgery the child underwent the first CI fitting session and continued to attend psychomotor and speech rehabilitation.…”

“…In patients with PRLTS, the SNHL is generally bilateral, symmetric, early onset and progressive, very often resulting in a severe-to-profound deficit [ 5 , 8 , 18 , 19 , 20 ]. Some authors have reported cases with an early onset acquired hearing loss that passes the newborn hearing screening [ 19 ].…”

“…Some authors have reported cases with an early onset acquired hearing loss that passes the newborn hearing screening [ 19 ]. In many cases, the audiometric curves are described to be upsloping [ 5 , 8 , 21 ] or flat [ 8 , 18 , 19 , 21 , 22 ].…”

“…In PRLTS, SNHL is generally reported to be due to a cochlear dysfunction, and only three cases due to a neural deficit (auditory neuropathy) are reported in the scientific literature, two cases with PRTLS5, associated with TWNK mutation [ 7 ] and a further case in PRTLS2, associated with HARS2 mutation [ 8 ].…”

Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants

“…On the contrary, mutations in the second ATG lead to lethality [ 48 ]. Mutations in HARS2 are associated to the Perrault syndrome, a disorder characterized by ovarian dysgenesis and sensorineural hearing loss [ 30 , 50 , 51 , 52 ]. To test the pathogenicity of alleged pathological mutations in HARS2 , the ability of the corresponding mutations introduced into HTS1 to complement the lethality of the deletion has been evaluated.…”