Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D‐bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease‐causing genes remain unidentified. We have expanded the spectrum of disease‐causing variants associated with Perrault syndrome.

Increasingly, mitochondria are being recognized as having an important role in fertility. Indeed in assisted reproductive technologies mitochondrial function is a key indicator of sperm and oocyte quality. Here, we review the literature regarding mitochondrial genetics and infertility. In many multisystem disorders caused by mitochondrial dysfunction death occurs prior to sexual maturity, or the clinical features are so severe that infertility may be underreported. Interestingly, many of the genes linked to mitochondrial dysfunction and infertility have roles in the maintenance of mitochondrial DNA or in mitochondrial translation. Studies on populations with genetically uncharacterized infertility have highlighted an association with mitochondrial DNA deletions, whether this is causative or indicative of poor functioning mitochondria requires further examination. Studies on the impact of mitochondrial DNA variants present conflicting data but highlight POLG as a particularly interesting candidate gene for both male and female infertility.

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Perrault syndrome (PS) is a genetically heterogeneous disorder characterized by primary ovarian insufficiency (POI) in females and sensorineural hearing loss in males and females. In many PS subjects, causative variants have not been found in the five reported PS genes. The objective of this study was to identify the genetic cause of PS in an extended consanguineous family with six deaf individuals. Whole exome sequencing (WES) was completed on four affected members of a large family, and variants and co-segregation was confirmed by Sanger sequencing. All hearing impaired individuals, including the proband, are homozygous for a pathogenic variant of CLDN14, but this only explains the deafness. The PS proband is also homozygous for a frameshift variant (c.1453_1454delGA, p.Glu485Lysfs*5) in exon 7 of SGO2 encoding shugoshin 2, which is the likely cause of her concurrent ovarian insufficiency. In mouse, Sgol2a encoding shugoshin-like 2a is necessary during meiosis in both sexes to maintain the integrity of the cohesin complex that tethers sister chromatids. Human SGO2 has not previously been implicated in any disorder, but in this case of POI and perhaps others, it is a candidate for unexplained infertility.

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Over the past two decades, significant technological advances have facilitated the identification of hundreds of genes associated with hearing loss. Variants in many of these genes result in severe congenital hearing loss with profound implications for the affected individual and their family. This review collates these advances, summarizing the current state of genomic knowledge in childhood hearing loss. We consider how current and emerging genetic technologies have the potential to alter our approach to the management and diagnosis of hearing loss. We review approaches being taken to ensure that these discoveries are used in clinical practice to detect genetic hearing loss as soon as possible to reduce unnecessary investigations, provide information about reproductive risks, and facilitate regular follow-up and early treatment. We also highlight how rapid sequencing technology has the potential to identify children susceptible to antibiotic-induced hearing loss and how this adverse reaction can be avoided.

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.

The objective of this study was to report the clinical and biological characteristics of two Perrault syndrome cases in a Moroccan family with homozygous variant c.1565C>A in the LARS2 gene and to establish genotype-phenotype correlation of patients with the same mutation by review of the literature. Whole-exome sequencing was performed. Data analysis was carried out and confirmed by Sanger sequencing and segregation. The affected siblings were diagnosed as having Perrault syndrome with sensorineural hearing loss at low frequencies; the female proband had primary amenorrhea and ovarian dysgenesis. Both affected individuals had a marfanoid habitus and no neurological features. Both patients carried the homozygous variant c.1565C>A; p.Thr522Asn in exon 13 of the LARS2 gene. This variant has already been reported as a homozygous variant in three other Perrault syndrome families. Both affected siblings of a Moroccan consanguineous family with LARS2 variants had low-frequency sensorineural hearing loss, marfanoid habitus, and primary ovarian insufficiency in the affected girl. According to the literature, this variant, c.1565C>A; p.Thr522Asn, can be correlated with low-frequency hearing loss. However, marfanoid habitus was been considered a nonspecific feature in Perrault syndrome, but we believe that it may be more specific than considered previously. This diagnosis allowed us to provide appropriate management to the patients and to provide more accurate genetic counseling to this family.