Perrault Syndrome Type 2 via the HARS2 Gene

Perrault syndrome is a sex-influenced disorder that is characterized by progressive, sensorineural deafness coupled with ovarian dysgenesis or premature ovarian failure (streak gonads), amenorrhea, and infertility in females. This syndrome often goes undetected until puberty or during child-bearing years (Pierce et al. 2011). Perrault syndrome also affects males and is mainly characterized by progressive hearing loss. Affected females are karyotypically 46,XX and infertile; affected males are 46,XY and fertile. Some patients diagnosed with Perrault syndrome also develop neurologic abnormalities, which include mild mental retardation, cerebellar ataxia, and disruptions involving the peripheral nervous system (Huyghe et al. 2006). Due to the clinical heterogeneity of this deafness syndrome, Perrault syndrome has been further classified into two types. Type I is described as static and does not present with neurologic disease, whereas type II is characterized by progressive neurologic disease.

Diagnosing Perrault syndrome in a male patient can be very challenging, especially in the absence of a sister that presents specific symptoms of the syndrome. The average age at diagnosis of Perrault syndrome in females is 22 years old, which is often ascertained by a delay in puberty and the development of sensorineural deafness. Hearing loss in Perrault syndrome is always bilateral, although the severity can be variable (ranging from mild to profound deafness). Ovarian dysgenesis occurs in all female Perrault syndrome patients and is often validated by amenorrhea; however, males do not show any gonadal defects. Approximately 50% of patients with Perrault syndrome show delayed growth, with height often below the third percentile.

Perrault syndrome follows an autosomal recessive pattern of inheritance and is caused by variants in the HARS2 gene, also known as PRLTS2, which has been localized to chromosomal band 5q31.3. The HARS2 gene encodes an enzyme called mitochondrial histidine-tRNA ligase, also known as histidine translase and histidyl-tRNA synthetase, which is involved in protein biosynthesis (Olsen et al. 2006). Histidyl-tRNA synthetase is responsible for ligating amino acids onto cognate tRNA molecules (Vester et al. 2013). There are approximately 20 tRNA synthetases that are grouped into two classes based on their primary structure and crystallographic features (Raben et al. 1992; Li et al. 2011). Aside from its involvement with Perrault syndrome, histidyl-tRNA synthetase is also recognized as a common target of autoantibodies in human autoimmune diseases such as polymyositis and dermatomyositism (Ascherman et al. 2002). Other frequent targets of autoantibodies include threonyl-, alanyl-, glycyl-, and isoleucyl-tRNA (Ge et al. 1994).

The HARS2 gene consists of 13 exons and is approximately 6.9 kb. The first two exons of the HARS2 gene encode for a 32-amino acid helical motif that has been conserved from prokaryotes to humans (Raebn et al. 1994). Other genes implicated in the development of Perrault syndrome include CLPP, HSD17B4, PRLTS2, PRLTS3, PRLTS4, and LARS2 (Jenkinson et al. 2013). Most cases of Perrault syndrome are simultaneously reported in at least two female members of a family. In cases where two brothers are involved, these individuals often present a relatively mild phenotype. The causative mutations in the HARS2 gene are mainly missense substitutions (Pierce et al. 2011).

In a study involving an 11-member nonconsanguineous family, all five affected siblings were compound heterozygotes for variants in the HARS2 gene (Pierce et al. 2011). The paternal allele c.598C>G led to an alternative splice that yielded two transcripts, HARS2 p.L200V and HARS2 p.200-211, whereas the maternal allele c.1102G>T encoded one transcript, HARS2 p.V368L. The affected family members therefore produced three HARS2 transcripts. In ten other families with Perrault syndrome, no HARS2 variants were detected, thus indicating a 17% detection rate in families with Perrault syndrome. The analytical sensitivity of bi-directional sequencing is high because all HARS2 causative mutations reported to date are detectable by this method.

This test provides full coverage of all coding exons of the HARS2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).