Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families

Rogers, Eli; Kerlan, V.; Delemer, Brigitte; Catteau-Jonard, Sophie; Reznik, Yves; Gompel, Anne; Cedrin, Isabelle; Guedj, A.M.; Grouthier, Virginie; Brue, Thierry; Pienkowski, Catherine; Bachelot, Anne; Chantot‐Bastaraud, Sandra; Rousseau, Alexandra; Simon, Tabassome; Kott, Esther; Siffroi, Jean‐Pierre; Touraine, Philippe; Christin-Maître, Sophie

doi:10.1016/j.fertnstert.2021.12.023

Cited by 18 publications

(6 citation statements)

References 56 publications

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“…Here, we performed whole exome sequencing in 20 young DOR patients and 5 women with normal ovarian reserve to explore the potential genetic mechanism of DOR. In the sample selection, most of the previous studies used peripheral blood as the sample source ( Wang et al, 2019 ; Liu et al, 2020 ; Rouen et al, 2022 ), which could detect the genomic variation, but the somatic mutation occurred locally in the ovary will not be detected. The most ideal experimental sample should be oocytes, but the oocytes of patients are so precious that they must be reserved for subsequent in vitro fertilization and cannot be used as sequencing samples.…”

Section: Discussionmentioning

confidence: 99%

“…In the sample selection, most of the previous studies used peripheral blood as the sample source ( Wang et al, 2019 ; Liu et al, 2020 ; Rouen et al, 2022 ), which could only detect genetic variations, while somatic mutations will not be detected. The most ideal experimental sample in our study would be oocytes, but the oocytes of patients are so precious that they must be reserved for subsequent in vitro fertilization and cannot be used as sequencing samples.…”

Section: Introductionmentioning

confidence: 99%

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Whole exome sequencing reveals novel variants associated with diminished ovarian reserve in young women

Liu

et al. 2023

Front. Genet.

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Background: Diminished ovarian reserve is one of the most important causes of female infertility. In the etiology study of DOR, besides age, it is known that chromosomal abnormality, radiotherapy, chemotherapy and ovarian surgery can result in DOR. For young women without obvious risk factors, gene mutation should be considered as a possible cause. However, the specific molecular mechanism of DOR has not been fully elucidated.Methods: In order to explore the pathogenic variants related to DOR, twenty young women under 35 years old affected by DOR without definite factors damaging ovarian reserve were recruited as the research subjects, and five women with normal ovarian reserve were recruited as the control group. Whole exome sequencing was applied as the genomics research tool.Results: As a result, we obtained a set of mutated genes that may be related to DOR, where the missense variant on GPR84 was selected for further study. It is found that GPR84Y370H variant promotes the expression of proinflammatory cytokines (TNF-α, IL12B, IL-1β) and chemokines (CCL2, CCL5), as well as the activation of NF-κB signaling pathway.Conclusion: In conclusion, GPR84Y370H variant was identified though analysis for WES results of 20 DOR patients. The deleterious variant of GPR84 could be the potential molecular mechanism of non-age-related pathological DOR through its role in promoting inflammation. The findings of this study can be used as a preliminary research basis for the development of early molecular diagnosis and treatment target selection of DOR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing reveals novel variants associated with diminished ovarian reserve in young women

Liu

et al. 2023

Front. Genet.

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“…Można tu wyróżnić badanie asocjacyjne całego genomu (GWAS) i sekwencjonowanie nowej generacji (NGS). Badania whole-genome association study (WGAS) ocenia związek występowania różnych wariantów genetycznych z rozwojem choroby [22] [18]. Część wariantów genetycznych odpowiedzialnych za POI udało się też zidentyfikować dzięki wykorzystaniu sekwencjonowaniu nowej generacji (NGS).…”

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Premature Ovarian Insufficiency - diagnostic and therapeutic challenges

HAWRANIK

TOMASIK

WARZYSZAK

et al. 2023

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Introduction and purpose: Premature Ovarian Insufficiency (POI) is a rare but serious disease diagnosed in about 1% of women before the age of 40. It is characterized by hypoestrogenism and an increase in the level of the follicle-stimulating hormone, which is associated with menstrual disorders, pregnancy failures and a reduced quality of life. The main causes of POI include a genetic background and autoimmune abnormalities, as well as increasingly jatrogenic factors. Care for patients is focused on hormone replacement therapy and infertility treatment. The aim of this review is to discuss current treatment methods, the impact of early diagnosis and the prevention of premature ovarian insufficiency, which affects the ability to have one's own offspring. The article also describes new methods of infertility treatment that are under investigation. Materials and methods: This literature review is based on articles published in the PubMed database from 2015 to 2022 using the following phrases: premature ovarian insufficiency, premature ovarian insufficiency stem cells State of knowledge: The only way to treat infertility in women with POI is egg donation. Currently, research is being conducted to achieve early diagnosis, introduce new treatment methods and reduce the number of iatrogenic forms of POI. Conclusion: The main problem for women diagnosed with POI is the difficulty or often impossibility of having their own children. Egg donation does not allow for the transfer of the patient's genetic material, and is also not available as a treatment option in some countries. For this reason, new methods for early diagnosis, treatment, and prevention of POI are being developed.

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“…New technologies, such as next-generation sequencing and whole-exome sequencing, have enhanced progress in identifying genetic causes for POI. A genetic cause is found for 7–50% of patients, although the percentages are likely to be exaggerated due to the poor variant curation in some of the published studies ( Bachelot et al , 2009 ; Jiao et al , 2012 , 2017 ; Shen et al , 2021 ; Heddar et al , 2022 ; Rouen et al , 2022 ; Tucker et al , 2022 ). Majority of POI cases remain undefined.…”

Section: Introductionmentioning

confidence: 99%

Association of genetic disorders and congenital malformations with premature ovarian insufficiency: a nationwide register-based study

et al. 2023

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STUDY QUESTION Are genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)? SUMMARY ANSWER A wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI. WHAT IS KNOWN ALREADY POI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7–15% of POI cases. STUDY DESIGN, SIZE, DURATION This population-based study included 5011 women diagnosed with POI in 1988–2017. The data were collected from various national registries and covers women with POI nationwide. PARTICIPANTS/MATERIALS, SETTING, METHODS We identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date. MAIN RESULTS AND THE ROLE OF CHANCE Of the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1–1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1–39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2–43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10–14 years old, OR 24.1, 95% CI 15.1–38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had. LIMITATIONS, REASONS FOR CAUTION Some women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers. WIDER IMPLICATIONS OF THE FINDINGS GD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations. STUDY FUNDING/COMPETING INTEREST(S) Oulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

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Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families

Cited by 18 publications

References 56 publications

Whole exome sequencing reveals novel variants associated with diminished ovarian reserve in young women

Whole exome sequencing reveals novel variants associated with diminished ovarian reserve in young women

Premature Ovarian Insufficiency - diagnostic and therapeutic challenges

Association of genetic disorders and congenital malformations with premature ovarian insufficiency: a nationwide register-based study

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