Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder ( PEX6 ), metabo
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ORIGINAL INVESTIGATION
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) Elena J. Tucker1,2 · Rocio Rius2,3 · Sylvie Jaillard4,5 · Katrina Bell6 · Phillipa J. Lamont7 · André Travessa8 · Juliette Dupont8 · Lurdes Sampaio9 · Jérôme Dulon10 · Sandrine Vuillaumier‑Barrot11,12 · Sandra Whalen13 · Arnaud Isapof14 · Tanya Stojkovic15 · Susana Quijano‑Roy16 · Gorjana Robevska1 · Jocelyn van den Bergen1 · Chloe Hanna1,17 · Andrea Simpson18 · Katie Ayers1,2 · David R. Thorburn2,3 · John Christodoulou2,3,19 · Philippe Touraine10 · Andrew H. Sinclair1,2 Received: 1 March 2020 / Accepted: 2 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 Q 10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.
Introduction Perrault syndrome is a rare genetic condition characterised by sensorineural hearing loss in both sexes, as well as ovarian dysfunction in females (Newman et al. 1993). Some patients, but not all, also have neurological signs such as intellectual disability, ataxia, and peripheral neuropathy Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02176-w) contains supplementary material, which is available to authorized users. * Elena J. Tucker [email protected] * Andrew H. Sinclair [email protected] Extended author information available on the last page of the article
(Newman et al. 2018). The degree of hearing loss, as well as ovarian dysfunction, can vary. Hearing loss ca
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