The HARS2 gene is mapped to chromosome 5q31.3, which contains 13 exons and spans approximately 7.9 kb. The HARS2 gene encodes the highly conserved mitochondrial histidyl tRNA synthetase, which is involved in mitochondrial protein translation[1, 2]. In 2011, HARS2 was first identified as a cause of Perrault syndrome by genome-wide linkage analysis and candidate gene sequencing [1]. Perrault syndrome is an autosomal recessive disorder with main clinical features of bilateral SNHL, a mild to profound degree of hearing loss, and ovarian dysgenesis in females. When the onset of moderate SNHL is in early childhood, it may present as progressive hearing loss. Ovarian dysfunction ranges from primary amenorrhea to primary ovarian insufficiency (POI), which can lead to infertility. Affected males, on the other hand, show normal pubertal development and are typically fertile[3].
Diagnosis of Perrault syndrome is often based on common clinical manifestations of SNHL in females and males as well as ovarian dysfunction in females with normal karyotypes [1, 4]. Further, this diagnosis should only be made after exclusion of other potential diagnoses with symptoms similar to those of Perrault syndrome. Perrault syndrome is uncommon, and approximately 100 affected individuals have been reported to date [4]. The disease is clinically and genetically heterogeneous, and some patients show neurological signs in addition to typical deafness and premature ovarian failure [4]. Due to the complex clinical phenotype of the disease, affected males without affected sisters are diagnosed with nonsyndromic deafness rather than Perrault syndrome. The diagnosis of Perrault syndrome is confirmed by the presence of biallelic pathogenic variants in one of six genes, such as CLPP, ERAL1, HARS2, HSD17B4, LARS2, and TWNK[1, 5–9]. Currently, these genes explain approximately 40% of the causes of Perrault syndrome, but the genetic bases of more than half the cases of Perrault syndrome remain unclear [4].
Only seventeen cases of HARS2 variants spanning nine families have been reported to date[1, 4, 10–12]. Due to its very low incidence and clinical heterogeneity, much information remains to be collected with regard to this variant. In the present study, two novel putative pathogenic variants of HARS2 were identified in two male individuals, from the same Chinese family, with autosomal recessive non-syndromic SNHL. These two cases and a review of the literature were used to explore the correlation between phenotype and the HARS2 genotype.