LARS2 variants can present as premature ovarian insufficiency in the absence of overt hearing loss

Anne Sophie Neyroud, Joëlle Rudinger-Thirion, Magali Frugier, Lisa G. Riley, Maud Bidet, Linda Akloul, Andrea Simpson, David Gilot, John Christodoulou, Célia Ravel, Andrew H. Sinclair, Marc Antoine Belaud-Rotureau, Elena J. Tucker, Sylvie Jaillard

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Premature ovarian insufficiency (POI) affects 1 in 100 women and is a leading cause of female infertility. There are over 80 genes in which variants can cause POI, with these explaining only a minority of cases. Whole exome sequencing (WES) can be a useful tool for POI patient management, allowing clinical care to be personalized to underlying cause. We performed WES to investigate two French sisters, whose only clinical complaint was POI. Surprisingly, they shared one known and one novel likely pathogenic variant in the Perrault syndrome gene, LARS2. Using amino-acylation studies, we established that the novel missense variant significantly impairs LARS2 function. Perrault syndrome is characterized by sensorineural hearing loss in addition to POI. This molecular diagnosis alerted the sisters to the significance of their difficulty in following conversation. Subsequent audiology assessment revealed a mild bilateral hearing loss. We describe the first cases presenting with perceived isolated POI and causative variants in a Perrault syndrome gene. Our study expands the phenotypic spectrum associated with LARS2 variants and highlights the clinical benefit of having a genetic diagnosis, with prediction of potential co-morbidity and prompt and appropriate medical care, in this case by an audiologist for early detection of hearing loss.

Original languageEnglish
Pages (from-to)453–460
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number4
Early online date1 Dec 2022
Publication statusPublished - Apr 2023


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