NR5A1 – 46,XY Complete Gonadal Dysgenesis

NR5A1 encodes steroidogenic factor-1 (SF-1), an orphan nuclear receptor critical for adrenal and gonadal development. Heterozygous pathogenic NR5A1 variants result in a spectrum of 46,XY disorders of sex development (DSD), with complete gonadal dysgenesis (CGD) representing one of the most severe phenotypes characterized by female external genitalia and rudimentary gonads. Genetic testing for NR5A1 variants is therefore integral to the diagnostic evaluation of 46,XY DSD.

Several independent case reports describe heterozygous in-frame and microdeletion alleles in NR5A1. A patient with CGD and a non-communicating rudimentary uterus carried c.132_134del (p.Asn44del)[PMID:39149602], while a de novo 1.54 Mb microdeletion encompassing NR5A1 was identified in another 46,XY CGD patient with developmental delay[PMID:24056159].

Multi-patient studies further establish autosomal dominant inheritance: exome sequencing in two unrelated CGD patients revealed de novo frameshift p.Gln206ThrfsTer20 and missense p.Arg313Cys variants, the latter in digenic combination with MAP3K1 variants[PMID:27169744]. In a cohort of 84 46,XY GD patients, seven heterozygous NR5A1 mutations—including missense (p.Tyr211Cys, p.Leu298Pro) and splice-site defects—were found in six unrelated individuals, all absent from controls[PMID:29190620].

The NR5A1 variant spectrum includes in-frame deletions, missense substitutions in the DNA-binding and ligand-binding domains, frameshifts, and splice-site variants. Recurrent alleles such as c.937C>T (p.Arg313Cys) have been observed, and oligogenic inheritance involving DHX37 and SRY may modulate phenotypic severity[PMID:39149602].

Functional assays support a loss-of-function mechanism: SF-1 knockout mice exhibit adrenal and gonadal agenesis, mirroring human CGD[PMID:11932325]. In vitro, frameshift and P-box mutants show impaired DNA binding, altered subcellular localization, and dominant-negative effects on transcriptional activation of target promoters, including MIS and CYP11A1[PMID:29190620][PMID:15070943].

Clinical Validity and Evidence Summary

• Overall ClinGen classification: Strong. Rationale: ≥12 unrelated CGD probands with heterozygous NR5A1 variants, de novo and familial occurrences, and consistent functional impairment.

Inheritance and Testing Implications

NR5A1-related CGD follows autosomal dominant inheritance with variable expressivity. Molecular testing should include sequence and dosage analysis of NR5A1 in 46,XY DSD, guiding genetic counseling, prognostic assessment, and personalized management.

Key Take-Home

Heterozygous NR5A1 variants are a well-established cause of autosomal dominant 46,XY complete gonadal dysgenesis, with robust genetic and functional evidence supporting clinical testing.

References

• Frontiers in medicine • 2024 • Case report: Rare heterozygous variant in the NR5A1 gene causing 46,XY complete gonadal dysgenesis with a non-communicating rudimentary uterus. PMID:39149602
• European journal of medical genetics • 2013 • 46,XY disorder of sex development and developmental delay associated with a novel 9q33.3 microdeletion encompassing NR5A1. PMID:24056159
• Sexual development • 2016 • Identification of NR5A1 Mutations and Possible Digenic Inheritance in 46,XY Gonadal Dysgenesis. PMID:27169744
• Hormone and metabolic research • 2017 • Four Novel NR5A1 Mutations in 46,XY Gonadal Dysgenesis Patients Including Frameshift Mutations with Altered Subcellular SF-1 Localization. PMID:29190620
• The Journal of clinical endocrinology and metabolism • 2002 • Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. PMID:11932325
• The Journal of clinical endocrinology and metabolism • 2004 • A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency. PMID:15070943

Evidence Based Scoring (AI generated)