Abstract
Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.
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Data availability
Described variants are submitted to ClinVar. Further data generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
WGS was performed as part of the Australian Genomics Health Alliance (Australian Genomics) project, funded by a National Health and Medical Research Council (NHMRC) Targeted Call for Research Grant (1113531). This work was supported by an NHMRC program Grant (1074258, to A.H.S.), and NHMRC fellowships (1054432 to E.J.T., 1062854 to A.H.S., 1155244 to D.R.T), and a CONACYT Postgraduate Research Scholarship (R.R). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program.
Funding
WGS was performed as part of the Australian Genomics Health Alliance (Australian Genomics) project, funded by a National Health and Medical Research Council (NHMRC) Targeted Call for Research Grant (1113531). This work was supported by an NHMRC program Grant (1074258, to A.H.S.), and NHMRC fellowships (1054432 to E.J.T., 1062854 to A.H.S., 1155244 to D.R.T), and a CONACYT Postgraduate Research Scholarship (R.R). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program.
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Procedures were in accordance with the ethical standards of the Human Research Ethics Committee of the Royal Children’s Hospital, Melbourne (HREC/22073). WGS was performed as part of the Mitochondrial Flagship study of the Australian Genomics Health Alliance research project, which also has Human Research Ethics Committee approval (HREC/16/MH251).
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Tucker, E.J., Rius, R., Jaillard, S. et al. Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM). Hum Genet 139, 1325–1343 (2020). https://doi.org/10.1007/s00439-020-02176-w
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DOI: https://doi.org/10.1007/s00439-020-02176-w