| Gene | Molecular role / compartment | Evidence status | Representative phenotype or variant evidence | Key source DOI / PMID |
|---|---|---|---|---|
| **CLPP** | Mitochondrial matrix peptidase; mitochondrial protein quality control | **Core established (2022 core set)** | Biallelic **CLPP** variants cause Perrault syndrome type 3 with SNHL and POI; human and mouse loss causes infertility/deafness/ataxia; recent Chinese series summarized **33 PRLTS3 patients**, with **97% hearing loss**, **55% neurologic disease**, **71% of females POI** (pqac-00000010, pqac-00000013, pqac-00000018) | Faridi 2022 DOI: **10.1007/s00439-021-02319-7**; Key 2024 DOI: **10.3390/biom14020241**; Key 2022/Cells 2023 DOI: **10.3390/cells12010052** |
| **ERAL1** | Mitochondrial 12S rRNA chaperone; small mitoribosomal subunit assembly | **Core established (2022 core set)** | Included among the eight genes with supporting evidence in the 2022 review; implicated in mitochondrial translation/ribosome assembly dysfunction in Perrault syndrome (pqac-00000010, pqac-00000007) | Faridi 2022 DOI: **10.1007/s00439-021-02319-7** |
| **GGPS1** | Lipid/isoprenoid synthesis; geranylgeranyl diphosphate synthase | **Core established (2022 core set)** | Included in the eight-gene core set; genomic sequencing review classified it among metabolic causes of Perrault syndrome (pqac-00000010, pqac-00000014) | Faridi 2022 DOI: **10.1007/s00439-021-02319-7**; Tucker 2020 DOI: **10.1007/s00439-020-02176-w** |
| **HARS2** | Mitochondrial histidyl-tRNA synthetase; mitochondrial translation | **Core established (2022 core set)** | Included in the eight-gene core set; Perrault syndrome review notes HARS2-associated disease often lacks neurologic features relative to other genes (pqac-00000010, pqac-00000007) | Faridi 2022 DOI: **10.1007/s00439-021-02319-7** |
| **HSD17B4** | Peroxisomal fatty-acid oxidation / steroid metabolism; peroxisome | **Core established (2022 core set)** | Included in the eight-gene core set; distinguished as a peroxisomal contributor to Perrault syndrome rather than a primary mitochondrial translation defect (pqac-00000010, pqac-00000007) | Faridi 2022 DOI: **10.1007/s00439-021-02319-7** |
| **LARS2** | Mitochondrial leucyl-tRNA synthetase; mitochondrial translation | **Core established (2022 core set)** | Biallelic **LARS2** mutations linked to premature ovarian failure and hearing loss in Perrault syndrome; repeatedly cited as a core mitochondrial translation gene (pqac-00000010, pqac-00000018) | Pierce 2013 DOI: **10.1016/j.ajhg.2013.03.007**; Faridi 2022 DOI: **10.1007/s00439-021-02319-7** |
| **RMND1** | Mitochondrial inner-membrane translation factor; couples mitochondrial transcript handling to translation | **Core established (2022 core set)** | Two adult sisters with compound heterozygous **RMND1** variants **c.583G>A (p.Gly195Arg)** and **c.818A>C (p.Tyr273Ser)** had SNHL, ovarian dysfunction, and chronic kidney disease, providing independent confirmation of causality (pqac-00000016, pqac-00000015) | Oziębło 2020 DOI: **10.3390/genes11091060** |
| **TWNK** | Twinkle mtDNA helicase; mitochondrial DNA maintenance / nucleoid | **Core established (2022 core set)** | Included in the eight-gene core set; recognized as an mtDNA maintenance cause of Perrault syndrome and auditory neuropathy-spectrum presentations in literature review (pqac-00000010, pqac-00000017) | Faridi 2022 DOI: **10.1007/s00439-021-02319-7** |
| **PRORP** | Mitochondrial RNase P catalytic subunit; mitochondrial tRNA 5′-processing | **Expanded-spectrum / newer established beyond 2022 core set** | Bi-allelic **PRORP** variants caused impaired mitochondrial tRNA processing with decreased protein levels, rescue by WT cDNA, and multisystem presentations including SNHL and POI; earlier family had **~35–45%** reduction in 5′-processed tRNA in RNase P assays (pqac-00000012) | Hochberg 2021 DOI: **10.1016/j.ajhg.2021.10.002**; preprint DOI: **10.1101/168252** |
| **TFAM** | Mitochondrial transcription factor A; mtDNA packaging/maintenance | **Expanded-spectrum / candidate** | Genomic sequencing paper highlighted **TFAM** among mtDNA maintenance/translation causes in Perrault syndrome pedigrees, but it was not part of the 2022 eight-gene core set (pqac-00000014, pqac-00000011) | Tucker 2020 DOI: **10.1007/s00439-020-02176-w** |
| **PEX6** | Peroxisome biogenesis ATPase; peroxisome | **Expanded-spectrum / candidate** | Genomic sequencing study identified **PEX6** as a peroxisomal molecular cause in individuals labeled Perrault syndrome, supporting expansion beyond classic mitochondrial genes (pqac-00000014, pqac-00000007) | Tucker 2020 DOI: **10.1007/s00439-020-02176-w** |
| **MRPS7** | Mitochondrial ribosomal small-subunit protein 7; mitoribosome | **Expanded-spectrum / candidate** | Compound heterozygous **MRPS7** variants **c.373A>T (p.Lys125*)** and **c.536G>A (p.Arg179His)** in a 25-year-old woman with hearing loss and POI; authors state this “validates” MRPS7 as a cause of syndromic POI/Perrault syndrome (pqac-00000011, pqac-00000005, pqac-00000006) | Kline 2022 DOI: **10.3390/genes13112113** |
| **MRPL50** | Mitochondrial ribosomal large-subunit protein; mitoribosome | **Expanded-spectrum / candidate** | Mentioned in the 2025 DAP3 study summary as part of the broader Perrault-spectrum literature involving mitochondrial ribosomal defects, but detailed primary evidence was not retrieved here (pqac-00000002) | Cited in summary as Bakhshalizadeh 2023 DOI: **10.1007/s00439-023-02563-z** |
| **DAP3 / MRPS29** | Mitoribosomal small-subunit protein / GTPase-related apoptosis factor; mitochondrion | **Expanded-spectrum / candidate** | Five unrelated individuals with bi-allelic **DAP3** variants had phenotypes ranging from classic Perrault syndrome (SNHL + ovarian insufficiency) to childhood neurometabolic disease; fibroblasts showed reduced MRPS29 and combined complex I/IV deficiency (pqac-00000009, pqac-00000002) | Smith 2025 DOI: **10.1016/j.ajhg.2024.11.007** |
| **MRPL43** | Mitochondrial ribosomal large-subunit protein; mitoribosome | **Possible emerging association only** | Listed by Open Targets disease-target mapping for Perrault syndrome, but no supporting primary paper was retrieved in the present evidence set (pqac-00000000) | No primary source retrieved here |
| **MRPL49** | Mitochondrial ribosomal large-subunit protein; mitoribosome | **Possible emerging association only** | Listed by Open Targets disease-target mapping for Perrault syndrome, but no supporting primary paper was retrieved in the present evidence set (pqac-00000000) | No primary source retrieved here |


*Table: This table separates the 2022 eight-gene core Perrault syndrome set from expanded-spectrum and candidate genes supported by later mitochondrial/peroxisomal studies. It is useful for knowledge-base curation because it links each gene to its molecular role, evidence tier, representative phenotype evidence, and source citations.*