Perrault Syndrome Type 3 and Deafness, Autosomal Recessive 8 (DFNB8) via the CLPP 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) 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; however, it is often underdiagnosed because hypogonadism is not always observed in male patients. 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 1 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. Male patients with Perrault syndrome may present with cerebellar ataxia combined with peripheral neuropathy, as well as azoospermia (Lieber et al. 2014).

Perrault syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic sequence variants in the caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) gene, also known as PRLTS3, which has been localized to chromosomal band 19p13.3 (Bross et al. 1995; Santagata et al. 1999). The CLPP gene encodes an endopeptidase that serves as a component of a mitochondrial ATP-dependent proteolytic complex that is involved in the stress signaling pathway (Kang et al. 2002). The CLPP protein is a stable heptamer without proteolytic activity, with a molecular weight of 169.2 kDa; however, in the presence of ATP, this heptamer changes in conformation and undergoes activation of its catalytic site (Kang et al. 2005). The CLPP gene consists of 6 exons and covers approximately 32 kb. Other genes implicated in the development of Perrault syndrome include HSD17B4 (PRLTS1), HARS2 (PRLTS2), and LARS2 (PRLTS4).

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, possibly because only one of the two major domains of the enzyme is affected (either the dehydrogenase or the hydratase domain). Only 3 causative mutations in the CLPP gene have been reported to date, which include two missense mutations and one splicing sequence variant (Jenkinson et al. 2013).

In a study involving three families consisting of a total of 14 family members (10 affected and 4 unaffected), pathogenic sequence variants were detected in all family members with Perrault syndrome type 3 (Jenkinson et al. 2013).

This test provides full coverage of all coding exons of the CLPP 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).