Idiopathic hypogonadotropic hypogonadism due to TACR3 p.K286R in the Maltese population

Abstract

Idiopathic Hypogonadotropic Hypogonadism (IHH) is a rare condition characterised by the lack of sexual development by the age of 18 due to low concentrations of gonadotropin releasing hormone. Previous studies have identified a number of genes associated with IHH, including the tachykinin 3 receptor (TACR3) gene. In a previous study, using high throughput sequencing, the TACR3 p.K286R variant was identified in a Maltese IHH patient together with a second variant in FGFR1, also associated with IHH, this is suggestive of oligogenic inheritance. To date the significance of the TACR3 p.K286R variant is still unknown. In this study, 600 cord blood DNA samples from the Maltese population were genotyped using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism, followed by frequency analysis to determine the frequency of the variant in the Maltese population. The minor allele frequency in the Maltese is 0.014 and the population is in Hardy-Weinberg equilibrium. The frequency of the variant is much higher than that reported for other non-Finish Europeans, indicating a possible founder effect for TACR3 p.K286R. This also suggests that either the variant is not pathogenic or that the inheritance of another variant in addition to TACR3 p.K286R is required for the development of the condition.