Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility

Jaillard, Sylvie; Sreenivasan, Rajini; Beaumont, Marc; Robevska, Gorjana; Dubourg, Christèle; Knarston, Ingrid; Akloul, Linda; Bergen, Jocelyn van den; Odent, Sylvie; Croft, Brittany; Jouve, G; Grover, Sonia; Duros, Solène; Pimentel, Céline; Belaud‐Rotureau, Marc‐Antoine; Ayers, Katie; Ravel, Célia; Tucker, Elena J.; Sinclair, Andrew H.

doi:10.1016/j.maturitas.2019.10.011

Cited by 30 publications

(21 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to the Human Gene Variant Database, 22 variants in the SF1 gene are associated with POI. 14 , 15 In a recent report, also milder phenotypes characterized by decreased ovarian reserve in women with NR5A1 variants have been described, 16 which suggests that mutations in this gene can cause a continuum of ovarian deficiency.…”

Section: Discussionmentioning

confidence: 99%

Different Clinical Manifestations Related to Subvirilization in Three XY Patients With the Same Pathogenic Variant of Steroidogenic Factor 1

Ochoa

Yankovic

Poggi

et al. 2021

AACE Clinical Case Reports

View full text Add to dashboard Cite

Objective During the prenatal period, steroidogenic factor 1 is required for the development of the adrenal glands and for gonadal determination and differentiation, and after birth, it regulates gonadal progenitor cell formation and their survival. Here, we describe the clinical phenotype of three 46,XY patients (2 brothers and an unrelated subject) with disorder of sex development due to the same genetic variant. Methods All patients underwent hormonal and pelvic ultrasound studies. Sequence analysis and deletion/duplication testing of a panel encompassing 8 genes ( AR, DHH, MAP3K1, NROB1, SRD5A2, SRY, WT1, and nuclear receptor subfamily 5, group A, member 1 [ NR5A1 ]) were performed in the index cases. All family members were tested for the presence of the NR5A1 variant. Results A variant previously described as likely pathogenic in NR5A1 (c.251G>A, p.Arg84His) that segregated in 1 family with different degrees of under-virilization was found. The family 1 index case (IV2) and his brother (IV3) had an external masculinization scale score of 5/12, but only the index case had Müllerian remnants; however, the family 2 patient had a milder score of 9/12. The older female relatives of family 1 who harbor this variant experienced premature menopause. Conclusion To our knowledge, this is the first report where the c.251G>A (p.Arg84His) variant is associated with the presence of Müllerian remnants in 46,XY subjects and primary ovarian insufficiency in 46,XX individuals. The segregation of this variant with clinical manifestations provides further evidence for considering it as pathogenic.

show abstract

Section: Discussionmentioning

confidence: 99%

Different Clinical Manifestations Related to Subvirilization in Three XY Patients With the Same Pathogenic Variant of Steroidogenic Factor 1

Ochoa

Yankovic

Poggi

et al. 2021

AACE Clinical Case Reports

View full text Add to dashboard Cite

show abstract

“…Prior exome-sequencing studies seeking to identify new variants associated with OF [ 22 , 30 , 58 ] focused on established genes associated with OF; in our study, DNA sequences in genes related to ovarian physiology exhibited proportionately fewer variants than remaining genes in the exome. Further, prior studies identified variants shared by a few patients with OF and did not include controls [ 22 , 29 , 31 , 32 , 59 , 60 ]. The prioritisation criteria used in our study ensure that variants are rare and are likely under purifying selective pressure based on the potential cumulative adverse effects of the variants on genetic fitness of the OF population at a functional level [ 25 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite advantages of WES, the large degree of genetic variation creates challenges in identifying meaningful changes. Therefore, strategies are needed to identify candidate variants that can be prioritised by predicted protein defects, frequency in the population, and evidence of evolutionary pressure including negative selection [ 22 , 28 , 29 , 30 , 31 , 32 ]. Existing studies often lack (1) negative controls (i.e., age-matched individuals without OF); (2) characterisation of genetic variation identified in genes not known to be associated with the phenotype of interest; and (3) implementation of machine learning strategies such as machine learning algorithms that provide a more comprehensive picture, as is required in reproductive precision medicine [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Machine Learning-Based Approach Highlights the Use of a Genomic Variant Profile for Precision Medicine in Ovarian Failure

Henarejos-Castillo

Alemán

Martinez-Montoro³

et al. 2021

JPM

View full text Add to dashboard Cite

Ovarian failure (OF) is a common cause of infertility usually diagnosed as idiopathic, with genetic causes accounting for 10–25% of cases. Whole-exome sequencing (WES) may enable identifying contributing genes and variant profiles to stratify the population into subtypes of OF. This study sought to identify a blood-based gene variant profile using accumulation of rare variants to promote precision medicine in fertility preservation programs. A case–control (n = 118, n = 32, respectively) WES study was performed in which only non-synonymous rare variants <5% minor allele frequency (MAF; in the IGSR) and coverage ≥ 100× were considered. A profile of 66 variants of uncertain significance was used for training an unsupervised machine learning model to separate cases from controls (97.2% sensitivity, 99.2% specificity) and stratify the population into two subtypes of OF (A and B) (93.31% sensitivity, 96.67% specificity). Model testing within the IGSR female population predicted 0.5% of women as subtype A and 2.4% as subtype B. This is the first study linking OF to the accumulation of rare variants and generates a new potential taxonomy supporting application of this approach for precision medicine in fertility preservation.

show abstract

“…Others include a polymorphism in the synaptonemal complex protein 2-like (SYCP2L) gene, which has been associated with both age at natural menopause and dosage of exogenous FSH required during COH and a polymorphism in the tumor protein 73 (TP73) gene associated with lower levels of AMH and lower AFC (146). Last, polymorphisms in several other genes have been found in small series of isolated and familial cases of DOR and POI but need validation in larger studies (126,147). The only one of these polymorphisms with prevalence data available was for NOBOX in individuals with POI from the Bouilly et al (144, 145) studies, however, they did cite population-level data on frequency of missense mutations, which were used for calculations (PR ¼ 2.915; CI 2.597-3.272 and PR ¼ 4.175; CI 3.729-4.676 for the two studies, respectively) ( Table 2).…”

Section: Single-nucleotide Polymorphismsmentioning

confidence: 99%

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

Nesbit

Jia

Singh³

et al. 2020

F&S Reviews

View full text Add to dashboard Cite

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.

show abstract

Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility

Cited by 30 publications

References 28 publications

Different Clinical Manifestations Related to Subvirilization in Three XY Patients With the Same Pathogenic Variant of Steroidogenic Factor 1

Different Clinical Manifestations Related to Subvirilization in Three XY Patients With the Same Pathogenic Variant of Steroidogenic Factor 1

Machine Learning-Based Approach Highlights the Use of a Genomic Variant Profile for Precision Medicine in Ovarian Failure

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

Contact Info

Product

Resources

About