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Non-syndromic primary ovarian insufficiency due to ovarian dysgenesis in 46,XX patients is an uncommon finding in the general population, even though several monogenic variants have been reported as causative factors. Here, we describe a 15-year-old patient diagnosed with gonadal dysgenesis possibly due to the interaction of three potentially pathogenic variants of genes involved in ovarian maturation, namely factor in the germline alpha (FIGLA), newborn ovary homeobox-encoding (NOBOX) and nuclear receptor subfamily 5 group A member 1 (NR5A1). We also describe a different degree of residual ovarian function within the proband's family, whose female members carry one to three demonstrated variations in the aforementioned genes in a clinical spectrum potentially dependent on the number of alleles involved. Our results support the hypothesis that the severity of the clinical picture of the proband, resulting in complete ovarian dysgenesis, may be due to a synergic detrimental effect of inherited genetic variants.

Background: Steroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator involved in the hypothalamic-pituitary-steroidogenic organ development. Recently, heterozygous mutations in NR5A1 were found may contribute to the male infertility aetiology. Here, we investigated the association of polymorphisms in NR5A1 gene with azoospermic men in Sichuan, China. Methods: We have performed the NR5A1 gene direct secquencing in a cohort of 102 well-characterised idiopathic Chinese azoospermic infertile men versus 103 fertile men, who were selected by Semen analysis, Karyotype analysis and Y-chromosomal AZF deletion screening. We identified two previously described missense p. Results: Gly146Ala (rs1110061; c.437 G>C) and p.Arg313His (c.938G>A), and the frequency of 437C ( [OR] 1.846, 95% [CI] 1.227-2.778, P=0.003), 437GC (OR =1.884 , 95% CI =1.037-3.422 , P =0.037 ) and 437CC (OR =3.586 , 95% CI =1.397-9.206 , P =0.006 ) were found to be increased significantly in azoospermic patients while no mutations in control .Moreover, one novel heterozygous p.Ser322ILe (c.965 G >A) missense mutation was found in 8 patients which highly conserved serine to isoleucine shown in the Beta strand domain on SF-1 protein. Conclusions: This is the first study, according to our knowledge, to investigate the association between the polymorphisms of NR5A1 gene and azoospermic men in China, and these results suggest that the Gly146Ala polymorphism may be a susceptibility factor for the azoospermic men in Sichuan, China.

Background and objectives: Endometrial tissue growth and its activity outside the uterus cause endometriosis. It has been suggested that various epigenetic deviations play a major role in the pathogenesis of endometriosis. Steroidogenic factor 1 (SF-1; NR5A1) is an essential transcription factor for estrogen biosynthesis in endometrial cells. The expression of SF-1 in endometriosis and lack of expression in normal endometrium is primarily determined by its promoter methylation. Here, we aimed to compare the methylation status of the SF-1 gene promoter region in women with endometriosis in comparison to healthy subjects. Methods: In the present case–control study, DNA was extracted from 25 endometrial tissue samples from women with endometriosis and 5 normal post-hysterectomy endometrium tissues which were collected from Tabriz hospitals including Vali-e-Asr, Taleghani, 29 Bahman and Shams in 2016. The obtained DNA samples were subjected to Bisulfite-treatment. Finally, the status of SF-1gene promoter methylation was evaluated by methylation specific PCR method. Statistical analyses including descriptive and inferential statistics were conducted using tables, bar charts by statistical software SPSS version 20 and independence test. Results: The methylation status of SF-1 gene promoter was decreased significantly in endometriosis samples (P

Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans‐activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute.

Background: Steroidogenic factor 1, encoded by the NR5A1 gene, is a key regulator of endocrine function within the hypothalamic-pituitary-steroidogenic axis. Both homozygous, compound heterozygous and heterozygous mutations in the NR5A1 gene may determine 46,XY disorders of sex development (DSD). Patients and Methods:NR5A1 gene sequencing was performed in a cohort of 6 patients with 46,XY DSD without specific diagnosis. Results: Heterozygous NR5A1 gene mutations were found in 2 girls, aged 0.5 years and 14 years. The older girl harbored the c.250C>T transition in exon 4 (p.Arg84Cys), previously reported in a Japanese girl. The younger girl presented a de novo novel exon 6 heterozygous frameshift mutation (c.1074dupG) in codon 359 associated with the p.Gly146Ala polymorphism the latter inherited from her father. This baby showed severe impairment of androgen secretion from the first months of life. Overt adrenal insufficiency did not occur, but the older girl showed subnormal cortisol peak after ACTH stimulation. Conclusions:NR5A1 gene mutations are a relatively frequent cause of 46,XY DSD in humans. Clear indications for management of these individuals remain elusive, mainly when diagnosis is made in infancy. Long-term monitoring of adrenal function should be recommended.

Background: Three novel heterozygous SF-1 gene mutations affecting multiple members of two unrelated families with a history of 46,XY disorders of sex development (DSD) and 46,XX ovarian insufficiency are described. Methods: Clinical and mutational analysis of the SF-1 gene in 9 subjects of two families. Results: Family 1 had 2 affected 46,XY DSD subjects. One, born with severe perineal hypospadias, was raised as a male, and presented normal adolescence. The other, born with ambiguous genitalia, uterus, and mild testicular dysgenesis, was raised as a female. A W279X heterozygous mutation and an intronic deletion (g3314-3317delTCTC (IVS 4 + 8) was found in the SF-1 gene. In family 2, 4/6 affected siblings had 46,XY DSD or hypospadias. An affected 46,XX sister had normal sexual development but increased FSH levels. The 37-year-old affected mother had entered menopause. An Y183X heterozygous mutation was detected. Conclusion: An extreme within-family phenotypic variability, ranging from severe prenatal undervirilization to normal pubertal development, was observed in 46,XY-affected siblings, indicating that other unknown factors might be involved in the phenotype. Low ovarian reserve and preserved fertility in 46,XX subjects can be observed in heterozygous SF-1 gene mutations.

Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics. Patients: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c. IVS3ds + 1delG in MRAP. Several important clinical and molecular insights emerged. Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future. Türk Pediatrik Endokrinoloji Araştırma Bursu- UPE-2014-2 Wellcome Trust/European Commission - 098513/Z/12/Z National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London European Commission - PIEF-GA-2012-328959

WOS: 000377212700036, PubMed ID: 26523528, Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics. Patients: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c. IVS3ds + 1delG in MRAP. Several important clinical and molecular insights emerged. Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future., Turkish Pediatric Endocrinology Research Grant [UPE-2014-2]; Wellcome TrustWellcome Trust [098513/Z/12/Z]; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London; European CommunityEuropean Community (EC) [PIEF-GA-2012-328959], This work was supported by Turkish Pediatric Endocrinology Research Grant UPE-2014-2. J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (Grant 098513/Z/12/Z), with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. T.G. is a European Community, Marie-Curie research fellow (Grant PIEF-GA-2012-328959).

Premature ovarian failure (POF) is a frequent pathology affecting 1-1.5% of women under 40 years old. Despite advances in diagnosing and treating human infertility, POF is still classified as being idiopathic in 50-80% of cases, strongly suggesting a genetic origin for the disease. Different types of autosomal and X-linked genetic anomalies can originate the phenotype in syndromic and non-syndromic POF cases. Particular interest has been focused on research into non-syndromic POF causative coding variants during the past two decades. This has been based on the assumption that amino acid substitutions might modify the intrinsic physicochemical properties of functional proteins, thereby inducing pathological phenotypes. In this case, a restricted number of mutations might originate the disease. However, like other complex pathologies, POF might result from synergistic/compensatory effects caused by several low-to-mildly drastic mutations which have frequently been classified as non-functional SNPs. Indeed, reproductive phenotypes can be considered as quantitative traits resulting from the subtle interaction of many genes. Although numerous sequencing projects have involved candidate genes, only a few coding mutations explaining a low percentage of cases have been described. Such apparent failure to identify aetiological coding sequence variations might have been due to the inherent molecular complexity of mammalian reproduction and to the difficulty of simultaneously analysing large genomic regions by Sanger sequencing.The purpose of this review is to present the molecular and cellular effects caused by non-synonymous mutations which have been formally associated, by functional tests, with the aetiology of hypergonadotropic non-syndromic POF. Considerations have also been included regarding the polygenic nature of reproduction and POF, as well as future approaches for identifying novel aetiological genes based on next generation sequencing (NGS). © 2015 The Author.