Advertisement

Journal of Assisted Reproduction and Genetics

, Volume 36, Issue 1, pp 39–45 | Cite as

Gene variants identified by whole-exome sequencing in 33 French women with premature ovarian insufficiency

  • Xiang Yang
  • Philippe Touraine
  • Swapna Desai
  • Gregory Humphreys
  • Huaiyang Jiang
  • Alexander Yatsenko
  • Aleksandar RajkovicEmail author
Genetics

Abstract

Purpose

To investigate the potential genetic etiology of premature ovarian insufficiency (POI).

Methods

Whole-exome sequencing (WES) was done on DNA samples from women diagnosed with POI. Mutations identified were analyzed by in silico tools and were annotated according to the guidelines of the American College of Medical Genetics and Genomics. Plausible variants were confirmed by Sanger sequencing.

Results

Four of the 33 individuals (12%) carried pathogenic or likely pathogenic variants, and 6 individuals carried variants of unknown significance. The genes identified with pathogenic or likely pathogenic variants included PMM2, MCM9, and PSMC3IP.

Conclusions

WES is an efficient tool for identifying gene variants in POI women; however, interpretation of variants is hampered by few exome studies involving ovarian disorders and the need for trio sequencing to determine inheritance and to detect de novo variants.

Keywords

Premature ovarian insufficiency Whole-exome sequencing Gene variants 

Notes

Acknowledgements

We thank the affected individuals for their participation in this research study on the genetics of premature ovarian insufficiency. We thank the Magee Clinical Genomic Laboratory at Magee-Womens Hospital, UPMC (Pittsburgh, PA), for the whole-exome sequencing.

Funding

This research was funded by the National Institute of Child Health and Human Development (R01HD070647 and R21HD074278, A.R.).

Compliance with ethical standards

The study was approved by the Institutional Review Board of University of Pittsburgh (PRO09080427). Informed consent was obtained from all individual participants in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10815_2018_1349_MOESM1_ESM.xlsx (32 kb)
ESM 1 (XLSX 31 kb)
10815_2018_1349_MOESM2_ESM.xlsx (43 kb)
ESM 2 (XLSX 42 kb)
10815_2018_1349_MOESM3_ESM.xlsx (16 kb)
ESM 3 (XLSX 16 kb)

References

  1. 1.
    Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606–14.CrossRefGoogle Scholar
  2. 2.
    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(6):609–35.CrossRefGoogle Scholar
  3. 3.
    De Vos M, Devroey P, Fauser BCJM. Primary ovarian insufficiency. Lancet. 2010;376(9744):911–21.CrossRefGoogle Scholar
  4. 4.
    Qin Y, Jiao X, Simpson JL, Chen Z-J. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015;21(6):787–808.CrossRefGoogle Scholar
  5. 5.
    Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014;124(1):193–7.Google Scholar
  6. 6.
    European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, et al. ESHRE guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926–37.CrossRefGoogle Scholar
  7. 7.
    Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, Surti U, et al. MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet. 2014;95(6):754–62.CrossRefGoogle Scholar
  8. 8.
    AlAsiri S, Basit S, Wood-Trageser MA, Yatsenko SA, Jeffries EP, Surti U, et al. Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest. 2015;125(1):258–62.CrossRefGoogle Scholar
  9. 9.
    Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26(5):589–95.CrossRefGoogle Scholar
  10. 10.
    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(5):405–24.CrossRefGoogle Scholar
  11. 11.
    1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.CrossRefGoogle Scholar
  12. 12.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.CrossRefGoogle Scholar
  13. 13.
    Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11.CrossRefGoogle Scholar
  14. 14.
    Walters-Sen LC, Hashimoto S, Thrush DL, Reshmi S, Gastier-Foster JM, Astbury C, et al. Variability in pathogenicity prediction programs: impact on clinical diagnostics. Mol Genet Genomic Med. 2015;3(2):99–110.CrossRefGoogle Scholar
  15. 15.
    Schiff M, Roda C, Monin M-L, Arion A, Barth M, Bednarek N, et al. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature. J Med Genet. 2017;54(12):843–51.CrossRefGoogle Scholar
  16. 16.
    Sparks SE, Krasnewich DM. PMM2-CDG (CDG-Ia). In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle; 1993.Google Scholar
  17. 17.
    Schollen E, Pardon E, Heykants L, Renard J, Doggett NA, Callen DF, et al. Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene. Hum Mol Genet. 1998;7(2):157–64.CrossRefGoogle Scholar
  18. 18.
    Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman JJ, et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet. 1997;16(1):88–92.CrossRefGoogle Scholar
  19. 19.
    Pérez-Dueñas B, García-Cazorla A, Pineda M, Poo P, Campistol J, Cusí V, et al. Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations. Eur J Paediatr Neurol. 2009;13(5):444–51.CrossRefGoogle Scholar
  20. 20.
    Yuste-Checa P, Gámez A, Brasil S, Desviat LR, Ugarte M, Pérez-Cerdá C, et al. The effects of PMM2-CDG-causing mutations on the folding, activity, and stability of the PMM2 protein. Hum Mutat. 2015;36(9):851–60.CrossRefGoogle Scholar
  21. 21.
    Le Bizec C, Vuillaumier-Barrot S, Barnier A, Dupré T, Durand G, Seta N. A new insight into PMM2 mutations in the French population. Hum Mutat. 2005;25(5):504–5.CrossRefGoogle Scholar
  22. 22.
    Lutzmann M, Grey C, Traver S, Ganier O, Maya-Mendoza A, Ranisavljevic N, et al. MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol Cell. 2012;47(4):523–34.CrossRefGoogle Scholar
  23. 23.
    Fauchereau F, Shalev S, Chervinsky E, Beck-Fruchter R, Legois B, Fellous M, et al. A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency. Clin Genet. 2016;89(5):603–7.CrossRefGoogle Scholar
  24. 24.
    Lutzmann M, Maiorano D, Méchali M. Identification of full genes and proteins of MCM9, a novel, vertebrate-specific member of the MCM2-8 protein family. Gene. 2005;362:51–6.CrossRefGoogle Scholar
  25. 25.
    Desai S, Wood-Trageser M, Matic J, Chipkin J, Jiang H, Bachelot A, et al. MCM8 and MCM9 nucleotide variants in women with primary ovarian insufficiency. J Clin Endocrinol Metab. 2017;102(2):576–82.Google Scholar
  26. 26.
    Zangen D, Kaufman Y, Zeligson S, Perlberg S, Fridman H, Kanaan M, et al. XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Am J Hum Genet. 2011;89(4):572–9.CrossRefGoogle Scholar
  27. 27.
    Tremblay JJ, Viger RS. A mutated form of steroidogenic factor 1 (SF-1 G35E) that causes sex reversal in humans fails to synergize with transcription factor GATA-4. J Biol Chem. 2003;278(43):42637–42.CrossRefGoogle Scholar
  28. 28.
    Janse F, de With LM, Duran KJ, Kloosterman WP, Goverde AJ, Lambalk CB, et al. Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI). Fertil Steril. 2012;97(1):141–6.e2.CrossRefGoogle Scholar
  29. 29.
    Dong J, Albertini DF, Nishimori K, Kumar TR, Lu N, Matzuk MM. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature. 1996;383(6600):531–5.CrossRefGoogle Scholar
  30. 30.
    Dixit H, Rao LK, Padmalatha V, Kanakavalli M, Deenadayal M, Gupta N, et al. Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure. Menopause. 2005;12(6):749–54.CrossRefGoogle Scholar
  31. 31.
    Zhao H, Qin Y, Kovanci E, Simpson JL, Chen Z-J, Rajkovic A. Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure. Fertil Steril. 2007;88(5):1474–6.CrossRefGoogle Scholar
  32. 32.
    Kovanci E, Rohozinski J, Simpson JL, Heard MJ, Bishop CE, Carson SA. Growth differentiating factor-9 mutations may be associated with premature ovarian failure. Fertil Steril. 2007;87(1):143–6.CrossRefGoogle Scholar
  33. 33.
    França MM, Funari MFA, Nishi MY, Narcizo AM, Domenice S, Costa EMF, et al. Identification of the first homozygous 1-bp deletion in GDF9 gene leading to primary ovarian insufficiency by using targeted massively parallel sequencing. Clin Genet. 2018;93(2):408–11.CrossRefGoogle Scholar
  34. 34.
    Su Y-Q, Sugiura K, Sun F, Pendola JK, Cox GA, Handel MA, et al. MARF1 regulates essential oogenic processes in mice. Science (80). 2012;335(6075):1496–9.CrossRefGoogle Scholar
  35. 35.
    McPherson E, Turner L, Zador I, Reynolds K, Macgregor D, Giampietro PF. Ovarian failure and dilated cardiomyopathy due to a novel lamin mutation. Am J Med Genet A. 2009;149A(4):567–72.CrossRefGoogle Scholar
  36. 36.
    Krauss CM, Turksoy RN, Atkins L, McLaughlin C, Brown LG, Page DC. Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N Engl J Med. 1987;317(3):125–31.CrossRefGoogle Scholar
  37. 37.
    Aittomäki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82(6):959–68.CrossRefGoogle Scholar
  38. 38.
    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 U S A. 2011;108(16):6543–8.CrossRefGoogle Scholar
  39. 39.
    Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD, et al. The genetic basis of mendelian phenotypes: discoveries, challenges, and opportunities. Am J Hum Genet. 2015;97(2):199–215.CrossRefGoogle Scholar
  40. 40.
    OMIM - Online Mendelian Inheritance in Man [Internet]. cited 2018 Feb 12. Available from: https://omim.org/

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Xiang Yang
    • 1
    • 2
    • 3
  • Philippe Touraine
    • 4
    • 5
  • Swapna Desai
    • 1
  • Gregory Humphreys
    • 6
  • Huaiyang Jiang
    • 1
  • Alexander Yatsenko
    • 1
  • Aleksandar Rajkovic
    • 7
    • 8
    Email author
  1. 1.Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research InstituteUniversity of PittsburghPittsburghUSA
  2. 2.The Third Xiangya HospitalCentral South UniversityChangshaChina
  3. 3.Department of Gynecology, The Second Xiangya HospitalCentral South UniversityChangshaChina
  4. 4.Department of Endocrinology and Reproductive Medicine, Centre des Maladies Endocriniennes Rares de la Croissance et du DéveloppementCentre des Pathologies Gynécologiques RaresParisFrance
  5. 5.Pitie Salpetriere HospitalSorbonne UniversitéParisFrance
  6. 6.Magee-Womens HospitalPittsburghUSA
  7. 7.Department of PathologyUniversity of CaliforniaSan FranciscoUSA
  8. 8.Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations