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.
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An encounter with the mild side of LARS2-associated Perrault syndrome and its implications on the diagnostic odyssey
European Journal of Human Genetics Open Access 24 January 2023
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The datasets generated and/or analyzed during the current study are contained within the manuscript or available from the corresponding author on reasonable request and within ethical constraints. The LARS2 variants have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/, SCV002099518 and SCV002099519).
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We thank the Bioinformatic department of CHU Rennes (UF Bioinformatique et Génétique Computationnelle, Service de Génétique Moléculaire et Génomique, Pr M. De Tayrac and Dr W. Carré) for helpful advice and technical assistance. Dr A. Meyer (otorhinolaryngologist at Polyclinique Sévigné, Cesson-Sévigné) performed audiology assessment. Some figures were created with BioRender.com.
This work was supported by a CHU Rennes grant (Appel à Projets Innovations 2019 to SJ), an Australian NHMRC program grant (1074258 to AHS), NHMRC fellowships (1054432 to EJT, 1062854 to AHS) and an Australian Mito Foundation grant (EJT). Part of this work was performed under the Rare Diseases Functional Genomics program, supported by the Luminesce Alliance—Innovation for Children’s Health, a not for profit cooperative joint venture between the Sydney Children’s Hospitals Network, the Children’s Medical Research Institute, and the Children’s Cancer Institute. It has been established with the support of the NSW Government to coordinate and integrate pediatric research. Luminesce Alliance is also affiliated with the University of Sydney and the University of New South Wales Sydney (LGR). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian government’s operational infrastructure support program. The Chair in Genomic Medicine awarded to JC is generously supported by The Royal Children’s Hospital Foundation.
The authors declare no competing interests.
Written informed consent was obtained from the patients. All procedures were in accordance with the ethical standards of the Ethics Committee of Rennes University Hospital and the French law.
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Neyroud, A.S., Rudinger-Thirion, J., Frugier, M. et al. LARS2 variants can present as premature ovarian insufficiency in the absence of overt hearing loss. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01252-1
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