Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Assisted Reproduction and Genetics
Published in: Journal of Assisted Reproduction and Genetics 1/2019

01-01-2019 | Genetics

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

Authors: Xiang Yang, Philippe Touraine, Swapna Desai, Gregory Humphreys, Huaiyang Jiang, Alexander Yatsenko, Aleksandar Rajkovic

Published in: Journal of Assisted Reproduction and Genetics | Issue 1/2019

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
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.CrossRefPubMed
3.
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.CrossRefPubMedPubMedCentral
5.
Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014;124(1):193–7.
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.CrossRef
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
9.
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.CrossRefPubMedPubMedCentral
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.CrossRef
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRef
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
40.
Metadata
Title
Gene variants identified by whole-exome sequencing in 33 French women with premature ovarian insufficiency
Authors
Xiang Yang
Philippe Touraine
Swapna Desai
Gregory Humphreys
Huaiyang Jiang
Alexander Yatsenko
Aleksandar Rajkovic
Publication date
01-01-2019
Publisher
Springer US
Published in
Journal of Assisted Reproduction and Genetics / Issue 1/2019
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI
https://doi.org/10.1007/s10815-018-1349-4

Other articles of this Issue 1/2019

Journal of Assisted Reproduction and Genetics 1/2019 Go to the issue

Letter to the Editor

Is it realistic to consider vitamin D as a follicular and serum marker of human oocyte quality?

Assisted Reproduction Technologies

The number of biopsied trophectoderm cells may affect pregnancy outcomes

Reproductive Physiology and Disease

Altered expression of the kisspeptin/KISS1R and neurokinin B/NK3R systems in mural granulosa and cumulus cells of patients with polycystic ovarian syndrome

Embryo Biology

Single blastomeres as a source of mouse embryonic stem cells: effect of genetic background, medium supplements, and signaling modulators on derivation efficiency

Genetics

Minimizing mosaicism: assessing the impact of fertilization method on rate of mosaicism after next-generation sequencing (NGS) preimplantation genetic testing for aneuploidy (PGT-A)

Genetics

Gonadotropin receptor variants are linked to cumulative live birth rate after in vitro fertilization