Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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 (, SCV002099518 and SCV002099519).


  1. Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH. Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic spectrum. Endocr Rev. 2016;37:609–35.

    Article  PubMed  Google Scholar 

  2. Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015;21:787–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tucker EJ, Grover SR, Robevska G, van den Bergen J, Hanna C, Sinclair AH. Identification of variants in pleiotropic genes causing “isolated” premature ovarian insufficiency: implications for medical practice. Eur J Hum Genet. 2018;26:1319–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kosaki R, Horikawa R, Fujii E, Kosaki K. Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms. Am J Med Genet A. 2018;176:404–8.

    Article  CAS  PubMed  Google Scholar 

  5. Riley LG, Rudinger-Thirion J, Frugier M, Wilson M, Luig M, Alahakoon TI, et al. The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy. Hum Mutat. 2020;41:1425–34.

    Article  CAS  PubMed  Google Scholar 

  6. van der Knaap MS, Bugiani M, Mendes MI, Riley LG, Smith DEC, Rudinger-Thirion J, et al. Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy. Neurology. 2019;92:e1225–e1237.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Perrault M, Klotz B, Housset E. [Two cases of Turner syndrome with deaf-mutism in two sisters]. Bull Mem Soc Med Hop Paris. 1951;67:79–84.

    CAS  PubMed  Google Scholar 

  8. Tucker EJ, Rius R, Jaillard S, Bell K, Lamont PJ, Travessa A, 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. 2020;139:1325–43.

  9. Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K, Morell RJ, et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet. 2013;92:605–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chatzispyrou IA, Alders M, Guerrero-Castillo S, Zapata Perez R, Haagmans MA, Mouchiroud L, et al. A homozygous missense mutation in ERAL1, encoding a mitochondrial rRNA chaperone, causes Perrault syndrome. Hum Mol Genet. 2017;26:2541–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hochberg I, Demain LAM, Richer J, Thompson K, Urquhart JE, Rea A, et al. Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations. Am J Hum Genet. 2021;108:2195–204.

  12. Demain LA, Antunes D, O’Sullivan J, Bhaskhar SS, O’Keefe RT, Newman WG. A known pathogenic variant in the essential mitochondrial translation gene RMND1 causes a Perrault-like syndrome with renal defects. Clin Genet. 2018;94:276–7.

    Article  CAS  PubMed  Google Scholar 

  13. Pierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM, et al. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci USA. 2011;108:6543–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pierce SB, Gersak K, Michaelson-Cohen R, Walsh T, Lee MK, Malach D, et al. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet. 2013;92:614–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, et al. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet. 2010;87:282–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dominguez-Ruiz M, Garcia-Martinez A, Corral-Juan M, Perez-Alvarez AI, Plasencia AM, Villamar M, et al. Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders. J Transl Med. 2019;17:290.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ullah F, Rauf W, Khan K, Khan S, Bell KM, de Oliveira VC, et al. A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss. Hum Genet. 2021;140:1733–51.

  18. Pan Z, Xu H, Tian Y, Liu D, Liu H, Li R, et al. Perrault syndrome: Clinical report and retrospective analysis. Mol Genet Genom Med. 2020;8:e1445.

    CAS  Google Scholar 

  19. Rubio Gomez MA, Ibba M. Aminoacyl-tRNA synthetases. RNA. 2020;26:910–36.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tucker EJ, Jaillard S, Grover SR, van den Bergen J, Robevska G, Bell KM, et al. TP63-truncating variants cause isolated premature ovarian insufficiency. Hum Mutat. 2019;40:886–92.

  21. Yao YN, Wang L, Wu XF, Wang ED. Human mitochondrial leucyl-tRNA synthetase with high activity produced from Escherichia coli. Protein Expr Purif. 2003;30:112–6.

    Article  CAS  PubMed  Google Scholar 

  22. Demain LA, Urquhart JE, O’Sullivan J, Williams SG, Bhaskar SS, Jenkinson EM, et al. Expanding the genotypic spectrum of Perrault syndrome. Clin Genet. 2017;91:302–12.

    Article  CAS  PubMed  Google Scholar 

  23. Perret V, Garcia A, Grosjean H, Ebel JP, Florentz C, Giege R. Relaxation of a transfer RNA specificity by removal of modified nucleotides. Nature. 1990;344:787–9.

    Article  CAS  PubMed  Google Scholar 

  24. Sohm B, Frugier M, Brule H, Olszak K, Przykorska A, Florentz C. Towards understanding human mitochondrial leucine aminoacylation identity. J Mol Biol. 2003;328:995–1010.

    Article  CAS  PubMed  Google Scholar 

  25. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Riley LG, Rudinger-Thirion J, Schmitz-Abe K, Thorburn DR, Davis RL, Teo J, et al. LARS2 variants associated with hydrops, lactic acidosis, sideroblastic anemia, and multisystem failure. JIMD Rep. 2016;28:49–57.

    Article  PubMed  Google Scholar 

  27. Morgan A, Lenarduzzi S, Spedicati B, Cattaruzzi E, Murru FM, Pelliccione G, et al. Lights and shadows in the genetics of syndromic and non-syndromic hearing loss in the Italian population. Genes. 2020;11.

  28. Someya S, Yamasoba T, Kujoth GC, Pugh TD, Weindruch R, Tanokura M, et al. The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase gamma. Neurobiol Aging. 2008;29:1080–92.

    Article  CAS  PubMed  Google Scholar 

  29. Chen A, Tiosano D, Guran T, Baris HN, Bayram Y, Mory A, et al. Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency. Hum Mol Genet. 2018;27:1913–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lerat J, Jonard L, Loundon N, Christin-Maitre S, Lacombe D, Goizet C, et al. An application of NGS for molecular investigations in Perrault syndrome: study of 14 families and review of the literature. Hum Mutat. 2016;37:1354–62.

    Article  CAS  PubMed  Google Scholar 

  31. Carminho-Rodrigues MT, Klee P, Laurent S, Guipponi M, Abramowicz M, Cao-van H, et al. LARS2-Perrault syndrome: a new case report and literature review. BMC Med Genet. 2020;21:109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gonzalez-Serrano LE, Chihade JW, Sissler M. When a common biological role does not imply common disease outcomes: disparate pathology linked to human mitochondrial aminoacyl-tRNA synthetases. J Biol Chem. 2019;294:5309–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. European Society for Human R, Embryology Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, et al. ESHRE guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31:926–37.

    Article  Google Scholar 

  34. Ren J, Wen L, Gao X, Jin C, Xue Y, Yao X. DOG 1.0: illustrator of protein domain structures. Cell Res. 2009;19:271–3.

    Article  CAS  PubMed  Google Scholar 

Download references


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


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.

Author information

Authors and Affiliations



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.

Corresponding authors

Correspondence to Elena J. Tucker or Sylvie Jaillard.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links