Spectrum and genotype-phenotype correlation of NR5A1 variants in 46,XY DSD: a systematic review and meta-analysis

NR5A1 encodes steroidogenic factor 1, a master regulator of adrenal and gonadal development. Pathogenic NR5A1 variants are among the most common genetic findings in 46,XY differences of sex development (DSD), yet the broad phenotypic spectrum remains incompletely defined.

This study aims to establish pooled estimates of key clinical outcomes and to clarify whether variant type predicts phenotype, pubertal course, or gender transition in NR5A1-related 46,XY DSD.

MEDLINE, Embase, and HGMD were systematically searched. Two reviewers independently screened, extracted, and appraised studies following the methodology of the Joanna Briggs Institute. Ninety-eight studies (312 individuals) were included; 35 series with ≥3 cases entered meta-analysis. Across studies, 85% presented atypical external genitalia and 15% female-like genitalia; sex of rearing was female in 54%. Spontaneous puberty occurred in 82% (95% CI: 45-96), and adrenal insufficiency in only 1.6%. All reported gender transitions were female to male (10%, 95% CI: 5-21). Missense variants represented 54%. Meta-regressions revealed no association between variant class and genital phenotype (odds ratio (OR): 1.25) or between phenotype and gender transition (OR: 0.46).

NR5A1-related 46,XY DSD is a dynamic condition with high rates of spontaneous virilisation (82%) and minimal adrenal involvement (1.6%). The absence of clear genotype-phenotype correlations and the occurrence of female-to-male gender reassignment support a conservative, longitudinal, patient-centred model of care. Given the unpredictability of individual outcomes, the quantitative estimates from this review support a shift towards evidence-based, longitudinal care that prioritises patient autonomy by deferring irreversible decisions.