ORPHA: 2855; DO: 0050857;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q31.3 | Perrault syndrome 2 | 614926 | Autosomal recessive | 3 | HARS2 | 600783 |
A number sign (#) is used with this entry because of evidence that Perrault syndrome-2 (PRLTS2) is caused by compound heterozygous mutation in the HARS2 gene (600783) on chromosome 5q31.
Perrault syndrome-2 (PRLTS2) is an autosomal recessive disorder characterized by sensorineural deafness in both males and females. Affected females have primary amenorrhea, streak gonads, and infertility, whereas affected males show normal pubertal development and are fertile (summary by Pierce et al., 2011).
For a discussion of genetic heterogeneity of Perrault syndrome, see PRLTS1 (233400).
Pallister and Opitz (1979) reported 3 sisters with ovarian dysgenesis and moderate to severe sensorineural deafness. The proband was a 13-year-old girl who lacked pubertal development and was found to have moderately severe hearing loss at age 3. She had some mild dysmorphic features, such as epicanthal folds and scrotal tongue. Pelvic examination showed infantile female external and internal genitalia with gonadal streaks. Two older sisters, ages 36 and 27 years, respectively, had a similar phenotype. Both had primary amenorrhea, sexual infantilism, streak gonads, and sensorineural hearing loss, although 1 had hearing loss first noted as an adult. Two older bothers in their thirties had early-onset sensorineural hearing loss but normal pubertal maturation and fertility. All females had normal 46,XX karyotypes. Both parents had normal hearing.
The transmission pattern of Perrault syndrome-2 in the family reported by Pallister and Opitz (1979) was consistent with autosomal recessive inheritance.
By genomewide linkage analysis of a family with Perrault syndrome originally reported by Pallister and Opitz (1979), Pierce et al. (2011) found linkage to a 4.142-Mb region on chromosome 5q31 between D5S479 and D5S2508 (Z lod score of 3.10).
In affected members of a family of European descent with Perrault syndrome, originally reported by Pallister and Opitz (1979), Pierce et al. (2011) identified compound heterozygosity for 2 mutations in the HARS2 gene (600783.0001 and 600783.0002). The mutations were found by linkage analysis followed by candidate gene sequencing. Functional studies showed that the mutations resulted in decreased enzyme activity, and knockdown of the HARS2 homolog in C. elegans caused severe gonadal defects and infertility. As the HARS2 gene encodes a histidyl-tRNA synthetase that functions in mitochondria, Pierce et al. (2011) speculated that aberrations of mitochondrial translation may affect mammalian dysgenesis.
Zou et al. (2020) identified compound heterozygous mutations in the HARS gene (R191Q, 600783.0003 and R208C, 600783.0004) in a Han Chinese patient (D2092) with isolated severe to profound sensorineural hearing loss. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations.
Pallister, P. D., Opitz, J. M. The Perrault syndrome: autosomal recessive ovarian dysgenesis with facultative, non-sex-limited sensorineural deafness. Am. J. Med. Genet. 4: 239-246, 1979. [PubMed: 517579] [Full Text: https://doi.org/10.1002/ajmg.1320040306]
Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc. Nat. Acad. Sci. 108: 6543-6548, 2011. [PubMed: 21464306] [Full Text: https://doi.org/10.1073/pnas.1103471108]
Zou, S., Mei, X., Yang, W., Zhu, R., Yang, T., Hu, H. Whole-exome sequencing identifies rare pathogenic and candidate variants in sporadic Chinese Han deaf patients. Clin. Genet. 97: 352-356, 2020. [PubMed: 31486067] [Full Text: https://doi.org/10.1111/cge.13638]