Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine

Heddar, Abdelkader; Oğur, Çağrı; Costa, Sabrina Da; Braham, Inès; Billaud-Rist, Line; Fındıklı, Necati; Bénéteau, Claire; Reynaud, Rachel; Khaled, Mahmoud; Legrand, Stéphanie; Marchand, Maud; Cédrin‐Durnerin, Isabelle; Cantalloube, Adèle; Peigné, Maëliss; Bretault, Marion; Dagher-Hayeck, Benedicte; Perol, Sandrine; Droumaguet, C.; Cavkaytar, Sabri; Nicolas-Bonne, Carole; Elloumi, Hanen; Khrouf, Mohamed; Rougier-LeMasle, Charlotte; Fradin, Mélanie; Boette, Elsa Le; Luigi, Perrine; Guerrot, Anne‐Marie; Ginglinger, Emmanuelle; Zampa, Amandine; Fauconnier, Anaïs; Auger, Nathalie; Paris, Françoise; Brischoux‐Boucher, Elise; Cabrol, Christelle; Brun, A.; Guyon, Laura; Berard, Melanie; Riviere, Axelle; Gruchy, Nicolas; Odent, Sylvie; Gilbert‐Dussardier, Brigitte; Isidor, Bertrand; Piard, Juliette; Lambert, Laëtitia; Hamamah, S.; Guedj, A.M.; Perrière, Aude Brac de la; Fernandez, H.; Raffin-Sanson, Marie-Laure; Polak, Michel; Létur, H.; Epelboin, Sylvie; Plu‐Bureau, Geneviève; Wołczyński, Sławomir; Hiéronimus, S.; Aittomäki, Kristiina; Catteau-Jonard, Sophie; Misrahi, Micheline

doi:10.1016/j.ebiom.2022.104246

Cited by 37 publications

(22 citation statements)

References 67 publications

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“…ELAVL type proteins (ELAVL2) have a role in many pathophysiological processes as well as in the regulation of mRNA. Recent research has revealed a connection between ELAVL2 and menopause and primary ovarian insufficiency (POI) [ 51 ]. For Mice lacking ELAVL2, are infertile and have follicle-free ovaries [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Unravelling driver genes as potential therapeutic targets in ovarian cancer via integrated bioinformatics approach

Beg,

Parveen,

Fouad

et al. 2024

J Ovarian Res

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Target-driven cancer therapy is a notable advancement in precision oncology that has been accompanied by substantial medical accomplishments. Ovarian cancer is a highly frequent neoplasm in women and exhibits significant genomic and clinical heterogeneity. In a previous publication, we presented an extensive bioinformatics study aimed at identifying specific biomarkers associated with ovarian cancer. The findings of the network analysis indicate the presence of a cluster of nine dysregulated hub genes that exhibited significance in the underlying biological processes and contributed to the initiation of ovarian cancer. Here in this research article, we are proceeding our previous research by taking all hub genes into consideration for further analysis. GEPIA2 was used to identify patterns in the expression of critical genes. The KM plotter analysis indicated that the out of all genes 5 genes are statistically significant. The cBioPortal platform was further used to investigate the frequency of genetic mutations across the board and how they affected the survival of the patients. Maximum mutation was reported by ELAVL2. In order to discover viable therapeutic candidates after competitive inhibition of ELAVL2 with small molecular drug complex, high throughput screening and docking studies were used. Five compounds were identified. Overall, our results suggest that the ELAV-like protein 2-ZINC03830554 complex was relatively stable during the molecular dynamic simulation. The five compounds that have been found can also be further examined as potential therapeutic possibilities. The combined findings suggest that ELAVL2, together with their genetic changes, can be investigated in therapeutic interventions for precision oncology, leveraging early diagnostics and target-driven therapy.

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Section: Discussionmentioning

confidence: 99%

Unravelling driver genes as potential therapeutic targets in ovarian cancer via integrated bioinformatics approach

Beg,

Parveen,

Fouad

et al. 2024

J Ovarian Res

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“…In this study, five variants in BMPR2 were found for the first time in seven patients with POI. It was reported that the majority of the BMPR2 variants identified in POI patients were located in cytoplasmic tail (amino acids 504–1038) of BMPR2 [ 30 , 31 ]. However, three out of the five variants identified here were localized in kinase domain (amino acids 203–503).…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing of 500 POI patients identified novel responsible monogenic and oligogenic variants

Luo

Tang

et al. 2023

J Ovarian Res

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Background Premature ovarian insufficiency refers to the loss of ovarian function before 40 years of age. The etiology is heterogeneous, and genetic factors account for 20–25% of cases. However, how to transform genetic findings to clinical molecular diagnose remains a challenge. To identify potential causative variations for POI, a next generation sequencing panel with 28 known causative genes of POI was designed, and a large cohort of 500 Chinese Han patients was screened directly. Pathogenic evaluation of the identified variants and the phenotype analysis were performed according to monogenic or oligogenic variants. Results A total of 14.4% (72/500) of the patients carried 61 pathogenic or likely pathogenic variants in 19 of the genes in the panel. Interestingly, 58 variants (95.1%, 58/61) were firstly identified in patients with POI. FOXL2 harbored the highest occurrence frequency (3.2%, 16/500), among whom presented with isolated ovarian insufficiency instead of blepharophimosis-ptosis-epicanthus inversus syndrome. Moreover, luciferase reporter assay confirmed variant p.R349G, which account for 2.6% of POI cases, impaired the transcriptional repressive effect of FOXL2 on CYP17A1. The novel compound heterozygous variants in NOBOX and MSH4 were confirmed by pedigree haplotype analysis, and digenic heterozygous variants in MSH4 and MSH5 were firstly identified. Furthermore, nine patients (1.8%, 9/500) with digenic or multigenic pathogenic variants presented with delayed menarche, early onset of POI and high prevalence of primary amenorrhea compared with those with monogenic variation(s). Conclusions The genetic architecture of POI has been enriched through the targeted gene panel in a large cohort of patients with POI. Specific variants in pleiotropic genes may result in isolated POI rather than syndromic POI, whereas oligogenic defects might have cumulative deleterious effects on the severity of POI phenotype.

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“…Despite the wide use of NGS in genomic medicine and identification of relevant genes, the investigation of POI is often limited to the screening of FMR1 premutation and BMP15 and GDF9 mutations [17]. Among genetic associations for POI are mutations in FMR2 , PGRMC1 and BMP15 genes on the X chromosome, and NR5A1 , FOXL2 , INHA , GDF9 , NOBOX , NANOS3 and FIGLα genes in autosomes, but further research is needed before their introduction in clinical practise [18 ▪▪ ]. Identifying a strong genetic association with POI would allow prompt POI diagnosis and menopausal prediction, offering the options to these women for preserving their fertility with assisted reproduction technologies.…”

Section: Discussionmentioning

confidence: 99%

The genetic background of female reproductive disorders: a systematic review

Doulgeraki

Papageorgopoulou

Iliodromiti

2023

Current Opinion in Obstetrics &Amp; Gynecology

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Purpose of reviewReproductive function is the interplay between environmental factors and the genetic footprint of each individual. The development in genetic analysis has strengthened its role in the investigation of female reproductive disorders, potential treatment options and provision of personalized care. Despite the increasing requirement of genetic testing, the evidence of the gene--disease relationships (GDR) is limited. We performed a systematic review exploring the associations between the most frequent female reproductive endocrine disorders associated with subfertility [including polycystic ovaries syndrome (PCOS), premature ovarian failure (POI) and hypogonadotropic hypogonadism] and their genetic background in order to summarize current knowledge. MethodsA systematic review of relevant literature in accordance with PRISMA guidelines was conducted until July 2022. Data sources that were used are PubMed and Embase. Recent findingsA total of 55 studies were included from the 614 articles identified in the original search. We identified 384 genes associated with one or more of the included female reproductive disorders. The highest number of genes was found to be associated with POI (N ¼ 209), followed by hypogonadotropic hypogonadism (N ¼ 88) and PCOS (N ¼ 87). Four genes, including FSHR, LHb, LEPR and SF1 were associated with multiple reproductive disorders implying common pathways in the development of those diseases.

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Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine

Cited by 37 publications

References 67 publications

Unravelling driver genes as potential therapeutic targets in ovarian cancer via integrated bioinformatics approach

Unravelling driver genes as potential therapeutic targets in ovarian cancer via integrated bioinformatics approach

Next-generation sequencing of 500 POI patients identified novel responsible monogenic and oligogenic variants

The genetic background of female reproductive disorders: a systematic review

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