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

European Journal of Human Genetics volume 31, pages 453–460 (2023)Cite this article

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Abstract

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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Fig. 1: Likely pathogenic LARS2 variants that co-segregate with POI.
Fig. 2: Audiological data of the proband and her sister.
Fig. 3: Pathogenic or likely pathogenic variants reported in ClinVar, LOVD, or HGMD Pro with DOG tool [34].

Data availability

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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Acknowledgements

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.

Funding

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.

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Author notes

  1. These authors contributed equally: Elena J. Tucker, Sylvie Jaillard.

Authors and Affiliations

  1. CHU Rennes, Service de Biologie de la Reproduction-CECOS, F-35033, Rennes, France

    Anne Sophie Neyroud, Célia Ravel & Marc-Antoine Belaud-Rotureau

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

    Anne Sophie Neyroud, Célia Ravel, Marc-Antoine Belaud-Rotureau & Sylvie Jaillard

  3. Université de Strasbourg, Architecture et Réactivité de l’ARN, CNRS, IBMC, Strasbourg, France

    Joëlle Rudinger-Thirion & Magali Frugier

  4. Rare Diseases Functional Genomics, Kids Research, The Children’s Hospital at Westmead and The Children’s Medical Research Institute, Sydney, NSW, Australia

    Lisa G. Riley

  5. Specialty of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Lisa G. Riley & John Christodoulou

  6. Clinique Mutualiste La Sagesse, Service of AMP, 35000, Rennes, France

    Maud Bidet

  7. CHU Rennes, Service de Génétique Clinique, CLAD Ouest, F-35033, Rennes, France

    Linda Akloul

  8. School of Allied Health, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC, Australia

    Andrea Simpson & Marc-Antoine Belaud-Rotureau

  9. College of Health and Human Services, Charles Darwin University, Darwin, NT, Australia

    Andrea Simpson

  10. CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, F-35033, Rennes, France

    David Gilot & Sylvie Jaillard

  11. INSERM U1242, COSS, Université Rennes 1, F-35032, Rennes, France

    David Gilot

  12. Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC, Australia

    John Christodoulou, Andrew H. Sinclair & Elena J. Tucker

  13. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia

    John Christodoulou, Andrew H. Sinclair & Elena J. Tucker

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  1. Anne Sophie Neyroud
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Contributions

EJT and SJ contributed to conception and design of the study. MABR, AHS, SJ, and EJT participated in the project supervision. ASN, MB, LA, and CR were involved in patients’ medical care. JRT, MF, LGR, and JC contributed to functional work. All authors contributed to the acquisition and/or analysis of data. ASN, EJT, DG, and SJ wrote the manuscript. All authors revised it critically and approved the final version.

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Correspondence to Elena J. Tucker or Sylvie Jaillard.

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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 31, 453–460 (2023). https://doi.org/10.1038/s41431-022-01252-1

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