An exome‐wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes

Álvarez-Mora, María Isabel; Todeschini, Anne‐Laure; Caburet, Sandrine; Perets, Lilach Peled; Milá, Montserrat; Younis, Johnny S.; Shalev, Stavit A.; Veitia, Reiner A.

doi:10.1111/cge.13803

Cited by 12 publications

(7 citation statements)

References 23 publications

(34 reference statements)

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“… 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 Desai et al., Alvarez-Mora et al., Fauchereau et al., França et al., Goldberg et al., Guo et al., Liu et al., Shen et al., Turkyilmaz et al., Wood-Trageser et al., Yang et al., and Jolly et al. 27 , 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 80 Born small for gestational age Tenenbaum-Rakover et al., Heddar et al. 25 , 30 Delayed puberty AlAsiri et al., Tenenbaum-Rakover et al., Bouali et al., Heddar et al.…”

Section: Resultsmentioning

confidence: 99%

“…As with other MCM components, MCM8 and MCM9 have been implicated in initiation of DNA replication, 7 , 8 , 9 , 10 as well as in meiosis, 9 , 11 , 12 , 13 , 14 homologous recombination (HR) 15 , 16 , 17 , 18 , 19 , 20 , 21 and mismatch repair (MMR). 20 , 22 , 23 Correspondingly, the number of studies describing the possible involvement of MCM8 and MCM9 in pathologies has increased enormously, with disrupting variants of the MCM8/MCM9 genes that follow an autosomal recessive inheritance pattern linked to infertility in both males and females, 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 as well as recently highlighted roles for the MCM8/MCM9 genes in polyposis, 23 , 37 , 38 (early onset) colorectal cancer (OMIM 114500 ) 23 , 37 , 38 and multiple other cancer types. 23 , 34 , 37 , 38 …”

Section: Introductionmentioning

confidence: 99%

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Molecular functions of MCM8 and MCM9 and their associated pathologies

Helderman¹,

Terlouw²,

Bonjoch³

et al. 2023

iScience

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular functions of MCM8 and MCM9 and their associated pathologies

Helderman¹,

Terlouw²,

Bonjoch³

et al. 2023

iScience

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“… ATM is associated with POI [178] Mcm9 mutants show primordial germ cell loss due to reduced proliferation, independently of Atm-Chek2-p21-p53 [179] . MCM9 variants associated with POI [180] , [181] Extra spindle pole bodies 1 (separase) plays a critical role in maintenance of sister chromatid cohesion and genome stability in PGCs [182] . Mad2l2 is required for PGCs development during epigentic reprogramming [183] .…”

Section: Genome Stability In Primordial Germ Cells and Other Proliferative Germ Cellsmentioning

confidence: 99%

Genome diversity and instability in human germ cells and preimplantation embryos

Shukla

Høffding

Hoffmann

2021

Seminars in Cell & Developmental Biology

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Genome diversity is essential for evolution and is of fundamental importance to human health. Generating genome diversity requires phases of DNA damage and repair that can cause genome instability. Humans have a high incidence of de novo congenital disorders compared to other organisms. Recent access to eggs, sperm and preimplantation embryos is revealing unprecedented rates of genome instability that may result in infertility and de novo mutations that cause genomic imbalance in at least 70% of conceptions. The error type and incidence of de novo mutations differ during developmental stages and are influenced by differences in male and female meiosis. In females, DNA repair is a critical factor that determines fertility and reproductive lifespan. In males, aberrant meiotic recombination causes infertility, embryonic failure and pregnancy loss. Evidence suggest germ cells are remarkably diverse in the type of genome instability that they display and the DNA damage responses they deploy. Additionally, the initial embryonic cell cycles are characterized by a high degree of genome instability that cause congenital disorders and may limit the use of CRISPR-Cas9 for heritable genome editing.

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“…Genetic defects at the basis of POI, which cover at least half of POI aetiology, have been investigated and mainly detected in genes with a role in meiosis, gonadal development, DNA repair, hormonal signalling or transcriptional regulation, thus identifying POI as a complex genetically heterogeneous disorder resulting from defects in multiple complementary pathways ( Bouilly et al , 2016 ). In recent years, array-comparative genomic hybridisation (array-CGH) or single-nucleotide polymorphism array (SNP-array) in cohorts of POI patients ( Aboura et al , 2009 ; Dudding et al , 2010 ; Ledig et al , 2010 ; Quilter et al , 2010 ; Knauff et al , 2011 ; McGuire et al , 2011 ; Zhen et al , 2013 ; Norling et al , 2014 ; Jaillard et al , 2016 ; Tšuiko et al, 2016 ; Bestetti et al , 2019 ) and next-generation sequencing targeted to multigene panels or to the whole exome sequencing (WES) mainly performed on familial cases have shed light on new candidate POI genes ( Caburet et al , 2014 ; de Vries et al , 2014 ; Qin et al , 2015 ; Bramble et al , 2016 ; Fauchereau et al , 2016 ; Carlosama et al , 2017 ; Moriwaki et al , 2017 ; He et al , 2019 ; Alvarez‐Mora et al , 2020 ). Furthermore, with the expanding application of gene panels and WES, data from several cohorts of patients have been processed in a search for pathogenic variants in genes known to be involved in POI pathogenesis or in ovarian function ( Fonseca et al , 2015 ; Laissue, 2015 ; Bouilly et al , 2016 ; Desai et al , 2017 ; Tucker et al , 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Targeted whole exome sequencing and Drosophila modelling to unveil the molecular basis of primary ovarian insufficiency

et al. 2021

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STUDY QUESTION Can a targeted whole exome sequencing (WES) on a cohort of women showing a primary ovarian insufficiency (POI) phenotype at a young age, combined with a study of copy number variations, identify variants in candidate genes confirming their deleterious effect on ovarian function? SUMMARY ANSWER This integrated approach has proved effective in identifying novel candidate genes unveiling mechanisms involved in POI pathogenesis. WHAT IS KNOWN ALREADY POI, a condition occurring in 1% of women under 40 years of age, affects women’s fertility leading to a premature loss of ovarian reserve. The genetic causes of POI are highly heterogeneous and several determinants contributing to its prominent oligogenic inheritance pattern still need to be elucidated. STUDY DESIGN, SIZE, DURATION WES screening for pathogenic variants of 41 Italian women with non-syndromic primary and early secondary amenorrhoea occurring before age 25 was replicated on another 60 POI patients, including 35 French and 25 American women, to reveal statistically significant shared variants. PARTICIPANTS/MATERIALS, SETTING, METHODS The Italian POI patients’ DNA were processed by targeted WES including 542 RefSeq genes expressed or functioning during distinct reproductive or ovarian processes (e.g. DNA repair, meiosis, oocyte maturation, folliculogenesis and menopause). Extremely rare variants were filtered and selected by means of a Fisher Exact test using several publicly available datasets. A case-control Burden test was applied to highlight the most significant genes using two ad-hoc control female cohorts. To support the obtained data, the identified genes were screened on a novel cohort of 60 Caucasian POI patients and the same case-control analysis was carried out. Comparative analysis of the human identified genes was performed on mouse and Drosophila melanogaster by analysing the orthologous genes in their ovarian phenotype, and two of the selected genes were fruit fly modelled to explore their role in fertility. MAIN RESULTS AND THE ROLE OF CHANCE The filtering steps applied to search for extremely rare pathogenic variants in the Italian cohort revealed 64 validated single-nucleotide variants/Indels in 59 genes in 30 out of 41 screened women. Burden test analysis highlighted 13 ovarian genes as being the most enriched and significant. To validate these findings, filtering steps and Burden analysis on the second cohort of Caucasian patients yielded 11 significantly enriched genes. Among them, AFP, DMRT3, MOV10, FYN and MYC were significant in both patient cohorts and hence were considered strong candidates for POI. Mouse and Drosophila comparative analysis evaluated a conserved role through the evolution of several candidates, and functional studies using a Drosophila model, when applicable, supported the conserved role of the MOV10 armitage and DMRT3 dmrt93B orthologues in female fertility. LARGE SCALE DATA The datasets for the Italian cohort generated during the current study are publicly available at ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/): accession numbers SCV001364312 to SCV001364375. LIMITATIONS, REASONS FOR CAUTION This is a targeted WES analysis hunting variants in candidate genes previously identified by different genomic approaches. For most of the investigated sporadic cases, we could not track the parental inheritance, due to unavailability of the parents’ DNA samples; in addition, we might have overlooked additional rare variants in novel candidate POI genes extracted from the exome data. On the contrary, we might have considered some inherited variants whose clinical significance is uncertain and might not be causative for the patients’ phenotype. Additionally, as regards the Drosophila model, it will be extremely important in the future to have more mutants or RNAi strains available for each candidate gene in order to validate their role in POI pathogenesis. WIDER IMPLICATIONS OF THE FINDINGS The genomic, statistical, comparative and functional approaches integrated in our study convincingly support the extremely heterogeneous oligogenic nature of POI, and confirm the maintenance across the evolution of some key genes safeguarding fertility and successful reproduction. Two principal classes of genes were identified: (i) genes primarily involved in meiosis, namely in synaptonemal complex formation, asymmetric division and oocyte maturation and (ii) genes safeguarding cell maintenance (piRNA and DNA repair pathways). STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Italian Ministry of Health grants ‘Ricerca Corrente’ (08C621_2016 and 08C924_2019) provided to IRCCS Istituto Auxologico Italiano, and by ‘Piano Sostegno alla Ricerca’ (PSR2020_FINELLI_LINEA_B) provided by the University of Milan; M.P.B. was supported by Telethon-Italy (grant number GG14181). There are no conflicts of interest.

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An exome‐wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes

Cited by 12 publications

References 23 publications

Molecular functions of MCM8 and MCM9 and their associated pathologies

Molecular functions of MCM8 and MCM9 and their associated pathologies

Genome diversity and instability in human germ cells and preimplantation embryos

Targeted whole exome sequencing and Drosophila modelling to unveil the molecular basis of primary ovarian insufficiency

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