Idiopathic hypogonadotropic hypogonadism due to FGFR1 p.Y132C in the Maltese population

Abstract

Idiopathic Hypogonadotropic Hypogonadism (IHH) is a rare genetic disorder, characterised by a lack of sexual maturation by the age of 18 years with decreased levels of circulating gonadotropins and testosterone and with no structural abnormalities in the hypothalamic-pituitary axis. Pathogenic mutations in several genes have been identified and are associated with its development, including mutations in FGFR1. Various loss-of-function mutations in this gene are mostly associated with Kallmann Syndrome. Locally, a specific variant in FGFR1 (p.Y132C) was identified in a single patient with IHH and so the likely pathogenicity of this variant was determined through this population study. In the 584 cord blood DNA samples tested using PCR and Restriction Enzyme (RE) digest, the FGFR1 p.Y132C variant was not identified in any of the samples. The rare occurrence of this FGFR1 p.Y132C variant in the general population significantly increases the likelihood that it is pathogenic. However, it does not necessarily mean that individuals with this variant will suffer from IHH since FGFR1 variants tend to exhibit incomplete penetrance which leads to a high variability in phenotypic expression. The individual suffering from IHH was part of the Malta NGS project in which 3 other variants in FGFR1 were identified (p.C650C, p.D630Y and p.K535R) in 3 separate individuals, not known to suffer from IHH, using high throughput sequencing. These variants are not reported in any databases and have not been associated with IHH to date.