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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)

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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.

Author information

Authors and Affiliations

  1. Reproductive Development Group, Murdoch Children’s Research Institute, Melbourne, Australia

    Elena J. Tucker, Gorjana Robevska, Jocelyn van den Bergen, Chloe Hanna, Katie Ayers & Andrew H. Sinclair

  2. Department of Paediatrics, University of Melbourne, Melbourne, Australia

    Elena J. Tucker, Rocio Rius, Katie Ayers, David R. Thorburn, John Christodoulou & Andrew H. Sinclair

  3. Brain and Mitochondrial Research Group, Murdoch Children’s Research Institute, Melbourne, Australia

    Rocio Rius, David R. Thorburn & John Christodoulou

  4. Service de Cytogénétique et Biologie Cellulaire, CHU Rennes, 35033, Rennes, France

    Sylvie Jaillard

  5. Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, 35000, Rennes, France

    Sylvie Jaillard

  6. Department of Bioinformatics, Murdoch Children’s Research Institute, Melbourne, Australia

    Katrina Bell

  7. Neurogenetic Unit, Royal Perth Hospital, Perth, WA, Australia

    Phillipa J. Lamont

  8. Serviço de Genética Médica, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Centro Académico de Medicina de Lisboa, Lisbon, Portugal

    André Travessa & Juliette Dupont

  9. Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Centro Académico de Medicina de Lisboa, Unidade de Endocrinologia Pediátrica, Lisbon, Portugal

    Lurdes Sampaio

  10. Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Centre des Pathologies Gynécologiques Rares, AP-HP, Sorbonne University Medicine, Paris, France

    Jérôme Dulon & Philippe Touraine

  11. AP-HP, Biochimie et Génétique, Hôpital Bichat-Claude Bernard, Paris, France

    Sandrine Vuillaumier-Barrot

  12. INSERM U1149, Paris, France

    Sandrine Vuillaumier-Barrot

  13. AP-HP, UF de Génétique Clinique, Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs, Hôpital Armand Trousseau, Paris, France

    Sandra Whalen

  14. Department Child Neurology and Reference Center for Neuromuscular Diseases “Nord/Est/Ile-de-France”, GRC ConCer-LD, UPMC Univ Paris 06, Sorbonne Universités, FILNEMUS, 75012, Paris, France

    Arnaud Isapof

  15. APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France

    Tanya Stojkovic

  16. Centre de Référence Maladies Neuromusculaires, Service de Neurologie, Réanimation et Réeducation Pédiatriques, Hôpital Raymond Poincaré (APHP Paris Saclay, UVSQ), Garches, France

    Susana Quijano-Roy

  17. Department of Paediatric and Adolescent Gynaecology, Royal Children’s Hospital, Melbourne, VIC, 3052, Australia

    Chloe Hanna

  18. School of Allied Health, La Trobe University, Melbourne, Australia

    Andrea Simpson

  19. Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia

    John Christodoulou

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  1. Elena J. Tucker
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  2. Rocio Rius
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  4. Katrina Bell
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  6. André Travessa
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  7. Juliette Dupont
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  8. Lurdes Sampaio
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  9. Jérôme Dulon
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  10. Sandrine Vuillaumier-Barrot
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  11. Sandra Whalen
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  16. Jocelyn van den Bergen
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  17. Chloe Hanna
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Corresponding authors

Correspondence to Elena J. Tucker or Andrew H. Sinclair.

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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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