New perspectives on the genetic causes of diminished ovarian reserve and opportunities for genetic screening: systematic review and meta-analysis

Abstract

Objective: To provide an update on single-gene mutations identified as causative for pathologic diminished ovarian reserve (DOR) to inform clinical screening recommendations. Evidence Review: A systematic review of the literature was performed in accordance with PRISMA guidelines using PubMed and EM-BASE databases. Only full-text articles in English were included and articles were excluded that did not relate to single-gene causes of pathologic DOR in humans. The search was supplemented using references of the included articles. Primary outcomes included prevalence ratios (PRs) for 12 genes associated with pathologic DOR. Result(s): A total of 550 articles were screened, with 108 articles included for review. Fifteen observational studies had prevalence data available for quantitative analysis. Elevated prevalence ratios were found in women with DOR for the FMR1 premutation and FMR2 mutations as well as single-nucleotide polymorphisms in the BMP15, GDF9, FSHR, and NOBOX genes. Although some studies have suggested an increased prevalence of BRCA1 and BRCA2 mutations in women with DOR, the prevalence in the controls in the included studies was elevated and PRs did not achieve statistical significance. Conclusion(s): Women diagnosed with DOR are at an increased risk of carrying mutations in FMR1, FMR2, and variants in BMP15, GDF9, FSHR, and NOBOX genes. Of these, the only gene identified as having the potential to cause significant deleterious effects in offspring is the FMR1 premutation, which supports current national screening guidelines. Further studies of BRCA1 and BRCA2 are needed to determine whether pathologic DOR might be associated with mutations in those genes.

Molecular Drivers of Developmental Arrest in the Human Preimplantation Embryo: A Systematic Review and Critical Analysis Leading to Mapping Future Research

“…Genetic factors are among the causes of POR. More specifically a recent meta-analysis reported that mutations in FMR1 , and FMR2 , along with polymorphisms in the BMP-15 , GDF-9 , in the gene encoding the receptor of FSH ( FSHR ) and in the NOBOX gene may present as a cause for POR [ 235 ]. The FMR1 gene is associated with fragile X syndrome in the offspring [ 236 ].…”

“…As mentioned above, BMP-15 mRNA levels in embryos have been positively associated with embryo viability. Furthermore, other candidate genes have also been investigated regarding their role in the pathophysiology of POR, including BRCA1 and BRCA2 [ 235 ], IGF-1 , IGF-2 , along with their respective receptors, AMH , LHCGR and GREM1 [ 239 ], however robust conclusions cannot yet be reached.…”

Ovarian reserve in obese patients: where do the eggs disappear?

“…При неэффективности возможна инициация фармакотерапии, а при наличии показаний -использование методов бариатрической хирургии. В научной литературе имеются данные об улучшении показателей фертильности, в частности АМГ, на фоне низкокалорийной диеты у пациенток с ожирением [35,36]. Аналогичные результаты были получены у пациенток после проведенной бариатрической операции, где исходный уровень АМГ у пациенток без СПКЯ составлял 1,35±0,76 нг/мл, а после вмешательства 6,23±1,47 нг/мл.…”

Identification of compound heterozygous variants in MSH4 as a novel genetic cause of diminished ovarian reserve

“…The understanding of the etiology of DOR is limited, with current evidence suggesting a complex interplay of genetic and environmental factors. Although variants in several genes have been associated with an increased risk for DOR, including FMR1 , FMR2 , AMHR2 , LHCGR , BMP15 , TR53 , GDF9 , FSHR , and NOBOX , the underlying genetic mechanism remains largely unknown [ 9 , 10 ]. And the identification of specific genetic causes for DOR is hindered by the complex inheritance pattern and the lack of large-scale genetic studies.…”