ESPE Abstracts (2014) 82 WG3.1

Genetic Variation in Human SF-1 (NR5A1): Clinical Consequences for Individuals, Families and Populations

John Achermann


UCL Institute of Child Health, London, UK


Steroidogenic factor-1 (SF-1, NR5A1) is a key regulator of adrenal and gonad development, and controls transcription of many genes in these endocrine axes. A role for SF-1/NR5A1 in human endocrine conditions was first established 15 years ago when rare individuals with adrenal hypoplasia and 46,XY DSD (testicular dysgenesis, Müllerian structures) were reported. Although it was felt that adrenal failure would be a key feature of SF-1 disruption, in the past decade it has emerged that variations in SF-1/NR5A1 are relatively frequently associated with a range of 46,XY DSD phenotypes in individuals who have normal adrenal function. These phenotypes range from 46,XY complete testicular dysgenesis, through varying degrees of hypospadias/undescended testes, to male factor infertility and potential progressive endocrine dysfunction. Changes in SF-1/NR5A1 are also associated with primary ovarian insufficiency in DSD families or in sporadic cases. Evidence suggesting a causative (or at least strongly-associative) role for SF-1/NR5A1 in DSD comes from the strong co-segregation of phenotype with genotype within families, the high rate of de novo dominant or sex-limited dominant inheritance, and ‘burden testing’ showing a much higher prevalence of SF-1/NR5A1 variation in DSD populations compared to controls. However, variable penetrance of phenotype is seen and an unexpected number of (non-validated) SF-1/NR5A1 changes are being described in so-called control population databases of exome sequencing (e.g. EVS, 1000 genomes). Are these artefacts, non-penetrant phenotypes or could these changes represent a pool of population infertility? How do we counsel families about progressive changes in endocrine function or the risk of POI? Will individuals with SF-1/NR5A1 changes be at risk of adrenal insufficiency, or features such as obesity, anxiety or hyposplenism reported in mice? Is the p.G146A polymorphism important in humans? How do we get better information about the complexities of SF-1-associated conditions to health professionals and families? These issues will be discussed.

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