Clinical characteristics and prevalence
The conditions that individuals who have NR5A1 variation may suffer from are:
- Atypical sexual development in a 46,XY individual (46,XY disorders of sex development (DSD) with or without adrenal insufficiency (AI))
- The formation of a testis (46,XX testicular DSD) or an ovotestis (ovotesticular DSD) in a 46,XX individual
- male infertility
- primary ovarian insufficiency (POI)
- spleen development abnormalities
NR5A1 variation is rare and numbers about total prevalence remain elusive even more so because of the 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
Most NR5A1 mutations occur de novo. This means that they are not transmitted from one of the parents but that the variant is built in by accident during parental germ cell development. Germ cell development requires different cycles of cell division of progenitor germ cells to create an adequate number of mature germ cells. Each of these cell divisions requires copying of the DNA and during this DNA replication errors (comparable with typo’s) can occur. However, NR5A1 variants can also be inherited, both from the mother as from the father. Mothers that carry a NR5A1 variant are at risk for developing POI. More rarely, paternal inheritance has been described, both in fathers without any clinical manifestations as in fathers with mild genital manifestations like hypospadias. The described NR5A1 variants are all so called loss-of-function variants. This means that the variant will result in a protein that has a decreased activity.