NR5A1

Inheritance Pattern: AD

Disease ID:MONDO:0060489

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0009299

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016281

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018393

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0010766

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:1060211

Submitter: ClinGen

*NR5A1* was first reported in relation to autosomal dominant NR5A1-related sex development disorder in 1999 (Achermann et al., PMID: 10369247). Pathogenic variants in *NR5A1* (encoding Steroidogenic Factor 1, SF-1) cause a wide clinical spectrum of reproductive and endocrine dysfunction. In 46,XY individuals, this ranges from complete sex reversal with female external genitalia and Müllerian structures to milder forms of under-virilization such as hypospadias or isolated infertility. In 46,XX individuals, the most frequent manifestation is primary ovarian insufficiency (POI) (PMID: 21078366). Although SF-1 is essential for adrenal development, clinical adrenal insufficiency is observed in only a minority of cases. The condition is characterized by autosomal dominant inheritance with notable phenotypic variability and incomplete penetrance. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism and inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity: 46XX sex reversal 4 (OMIM:617480), 46XY sex reversal 3 (OMIM:612965), premature ovarian failure 7/adrenocortical insufficiency (OMIM:612964), spermatogenic failure 8 (OMIM:613957). Nineteen variants (including missense, nonsense, frameshift) that have been reported in 27 probands in 6 publications (PMIDs: 27378692, 20887963, 23299922, 40882352, 37409232, 29027299) are included in this curation. The genetic evidence for *NR5A1* includes variants that are distributed across critical functional domains of the protein, specifically the Zinc-finger DNA-binding domain (DBD) and the Ligand-binding domain (LBD). Multiple de novo occurrences have been documented in individuals with severe 46,XY differences of sex development (DSD) and adrenal insufficiency, providing strong evidence for pathogenicity. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. Segregation of *NR5A1* variants with disease have been demonstrated in multiple families, with affected individuals showing variable expressivity ranging from complete 46,XY sex reversal and adrenal insufficiency to milder phenotypes such as hypospadias, infertility, or isolated primary ovarian insufficiency in 46,XX individuals. Reduced and incomplete penetrance has also been observed (PMID: 33296094), consistent with prior reports and known biological roles of SF-1 in gonadal and adrenal development. Notably, the same heterozygous variant may result in 46,XY sex reversal in a proband while being present in a fertile, phenotypically 'normal' father (PMID: 27378692). Despite this variability, the enrichment of rare, damaging variants in affected cohorts compared to population databases (e.g., gnomAD) strongly supports the association. This gene-disease relationship is also supported by experimental evidence, including animal models, expression studies, and in vitro functional assays (PMIDs: 9774680, 11124111, 26269506, 22419830, 18703422, 8187173, 37494420). *NR5A1* encodes steroidogenic factor-1 (SF-1), a nuclear receptor that regulates adrenal and gonadal development and steroidogenic function (PMID: 20595937). Consistent with this role, Nr5a1 knockout in mice causes complete adrenal and gonadal agenesis, leading to 46,XY sex reversal with female external genitalia and presence of Müllerian structures (PMID: 18987494). At the molecular level, SF-1 cooperates with SRY-related factor SOX9 to activate Anti-Müllerian Hormone (AMH) transcription in Sertoli cells (PMID: 9774680), a crucial step for Müllerian duct regression during male differentiation. SF-1 function is dosage-sensitive, as demonstrated by hypomorphic mouse models. Nr5a1 mutant male mice with partial SF-1 expression show signs of androgen insufficiency – including cryptorchidism, impaired spermatogenesis, and undervirilized genitalia – due to disrupted Leydig cell development (PMID: 26269506). In females, SF-1 is essential for ovarian function: granulosa cell-specific SF-1 knockout mice have hypoplastic ovaries with reduced follicle number, absent corpora lutea, and infertility (PMID: 18703422), and prenatal ovarian depletion of SF-1 dramatically reduces the primordial follicle reserve by increasing oocyte loss (PMID: 37494420). These findings establish SF-1’s critical role in forming the ovarian reserve and correlate with 46,XX primary ovarian insufficiency observed in *NR5A1*-haploinsufficient women. Finally, functional assays of patient-derived *NR5A1* variants support their loss-of-function impact: several missense mutations identified in 46,XY DSD or idiopathic male infertility significantly impair SF-1’s transcriptional activity on target promoters in vitro (PMID: 20887963). Together, this experimental evidence solidifies the role of *NR5A1* in adrenal and gonadal development and links its dysfunction to disorders of sex development, adrenal insufficiency, ovarian failure, and infertility. In summary, there is definitive evidence supporting the relationship between *NR5A1* and NR5A1-related sex development disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Male Infertility GCEP on January 21, 2026 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0013066

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0017576

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0010765

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016674

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013504

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013065

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019852

Submitter: PanelApp Australia