Clinical characteristics and prevalence
The main phenotypes associated with NR5A1 variation are:
- 46,XY disorders of sex development (DSD)
- 46,XX testicular and ovotesticular DSD
- male infertility
- primary ovarian insufficiency (POI)
- adrenal insufficiency (AI)
- spleen development abnormalities
NR5A1 variation is rare and prevalence estimations are unavailable even more so due to extensive intra- and interfamilial phenotypic variability. More specifically, NR5A1 variants explain approximately 10-15% of all 46,XY DSD cases and 1.4-1.6% of sporadic POI cases.
Molecular characteristics and inheritance
The NR5A1 gene is located on chromosome 9 (9q33.3) and has 7 exons of which the first is non-coding. NR5A1 belongs to the nuclear receptor (NR) transcription factor family. In general NRs dimerize and translocate to the nucleus upon ligand binding, however NR5A1 is known to be an orphan NR, meaning that no ligand has been identified (yet). Most NR5A1 mutations are heterozygous de novo variants, however a homozygous missense mutation has been described in a patient with 46,XY DSD and AI and recently a homozygous frameshift deletion has been identified in a patient with isolated 46,XY DSD. Approximately one third of mutations are maternally inherited and paternal transmission has been rarely described. The described variants have a loss-of-function effect, perturbing DNA binding or transcriptional activation.