A novel STAG3 variant associated with primary ovarian insufficiency

INTRODUCTION

Primary ovarian insufficiency (POI) is characterized by ovarian dysfunction leading to reduced fertility in women under 40 years of age. For the diagnosis, there must be 4–6 months of amenorrhea in a woman under the age of 40 years with elevated gonadotropins and low estradiol.^[1] POI contributes to the causes of primary and secondary amenorrhea. Symptoms are similar to those of postmenopausal, such as menstrual irregularities and oligomenorrhea, and menopausal-like symptoms such as hot flashes, vaginal dryness, mood changes, and decreased bone density. Fertility issues are often a key concern, as women with POI may have difficulty conceiving due to low ovarian follicle reserve. In cases of primary amenorrhea, delayed or incomplete breast development may be observed. Diagnosing POI in adolescents can be delayed as irregular menstrual cycles can either indicate early adolescence or early POI.^[2]

POI occurs in approximately 1% of women who have not reached 40 years of age. The frequency is roughly 4–8% in women experiencing secondary amenorrhea and 10–28% in cases of primary amenorrhea.^[3,4] The etiology of POI is heterogeneous, and known causes include genetic factors, iatrogenic (such as surgery, chemotherapy and radiotherapy), autoimmune disorders, and idiopathic causes.^[1] The overall prevalence of POI associated with genetic mutations is approximately 20–25%.^[2,5] Chromosomal abnormalities such as monosomy or mosaic forms of trisomy X and fragile X syndrome are well-established causes of POI, and their frequency is approximately 10–13%.^[6] Mutations of >60 genes have been linked with POI.^[7] One gene of interest is STAG3, and mutation in this gene leads to abnormal folliculogenesis and, eventually, POI.^[5] STAG3 encodes a protein, which functions as a subunit of the cohesin complex in meiosis.^[5,8] The mutations in STAG3 gene are uncommon and are seen in ethnicities such as Middle Eastern, Asian, and Caucasian populations where consanguineous marriages are high.^[8-11]

CASE REPORT

A 15-year and 7-month-old Kashmiri girl with normal perinatal and postnatal development presented with the parental concern regarding delayed menarche. The patient’s mother reported the development of breast buds 4 years ago, which progressed for 2 years before stagnating. Pubic and axillary hair appeared 4 years ago. There were no concerns regarding short stature. There was no history of muscle weakness, a round face, easy bruising, headache, or visual field defects. She was born of non-consanguineous marriage, but there was a history of skin cancer and eye cancer each in two maternal uncles and kidney disease in one maternal uncle and maternal aunt.

On examination, the patient’s height was 158.3 cm (50^th–75^th percentile), weight 55.5 kg (75^th percentile), Tanner staging A3, P3, B2, normal female external genitalia, no physical features of Turner syndrome, and no thyromegaly. Systemic examination was unremarkable. Laboratory investigations revealed elevated follicle-stimulating hormone (FSH) at 78.3 mIU/mL and luteinizing hormone (LH) at 20.3 mIU/mL, with low estradiol (E2) <11.8 pg/mL and anti-Mullerian hormone (AMH) <0.02 ng/mL. Thyroid-stimulating hormone (TSH) and cortisol levels were within normal ranges. Magnetic resonance imaging (MRI) and ultrasound visualized the hypoplastic uterus (endometrial thickness 2 mm), but the ovaries were not visualized.

Based on the clinical presentation and laboratory findings, a provisional diagnosis of “46,XX gonadal dysgenesis” was considered. Karyotype was 46,XX and whole genome sequencing revealed a STAG3 mutation. In this case, homozygous missense variant in exon 9 of the STAG3 gene (chr7: g.100195367T>C; Depth: 124×) that results in the amino acid substitution of serine for phenylalanine at codon 309 (p.Phe309Ser; ENST00000615138.5) was detected. The observed variant lies in the “Regulator of chromosome condensation 1 (RCC1) repeat” domain of the STAG3 protein. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), and gnomdAD (v2.1), TOPMed. This STAG3 variant is classified as a variant of uncertain significance.

DISCUSSION

POI is a complex condition that results in diminished ovarian function before the age of 40 years, with genetic factors contributing to 20–25% of cases.^[3] STAG3 gene mutations are among the recognized causes of POI, which encodes a crucial component of the cohesin complex. This complex plays an essential role in chromosome cohesion during meiosis, and disruption of this process can lead to errors in chromosomal segregation, resulting in gonadal dysfunction and ovarian insufficiency.^[7,12]

The present case of a 15-year and 7-month-old Kashmiri girl with delayed menarche and clinical features of gonadal dysgenesis is significant due to the identification of a novel homozygous missense mutation in STAG3, c.926T>C (p.Phe309Ser). This mutation is located in the RCC1 domain of the STAG3 protein. The RCC1 domain is vital for the cohesin complex’s integrity during meiosis, and mutations within this region could disrupt chromosomal segregation. Specifically, the substitution of phenylalanine with serine at codon 309 likely alters the protein’s structural stability or folding, impairing its function in maintaining sister chromatid cohesion during oocyte development. This disruption ultimately leads to premature depletion of ovarian follicles, manifesting as POI.

The STAG3 mutation spectrum in POI is diverse, with various mutations identified across different ethnicities [Table 1].^[11-18] Notably, the p.Phe309Ser mutation found in this patient represents a novel addition to the Asian genetic landscape, as previously reported STAG3 mutations have been more commonly identified in populations from the Middle East and Europe. For instance, Caburet et al.^[12] described a c.968delC mutation in a Middle Eastern Palestinian cohort, while Colombo et al.^[13] reported a c.677C>G mutation in Asian individuals. This expanding catalog of STAG3 mutations underscores the gene’s importance in ovarian function across diverse populations. Comparing this case with previous reports highlights the heterogeneity of STAG3 mutations in terms of both the nature of the mutations and the ethnic backgrounds of the affected individuals. For example, mutations such as c.291dupC (p.Asn98Glnfs*2) in a Brazilian patient^[9] and c.877_885del (p.293_295del) in a Chinese individual^[11] demonstrate the widespread occurrence of STAG3 mutations. The p.Phe309Ser mutation identified in this patient contributes to the understanding of POI pathogenesis, particularly within Asian populations, where consanguinity may increase the risk of autosomal recessive mutations such as this one.

CONCLUSION

This case adds to the growing evidence of the genetic basis of POI and emphasizes the importance of STAG3 mutations in its pathogenesis. The discovery of the c.926T>C (p.Phe309Ser) variant in an Asian female with delayed menarche underscores the importance of considering genetic testing in young patients presenting with unexplained gonadal dysgenesis. As more cases of POI linked to STAG3 mutations are reported across different ethnicities, a deeper understanding of the gene’s role in ovarian biology and its diverse phenotypic presentations will emerge, guiding more personalized approaches to management and treatment. Further studies are needed to delineate the precise molecular consequences of the p.Phe309Ser mutation and its impact on cohesin complex function.