Additional mutation in PROKR2 and phenotypic differences in a Kallmann syndrome/normosmic congenital hypogonadotropic hypogonadism family carrying FGFR1 missense mutation

Congenital hypogonadotropic hypogonadism (CHH) is a genetically and clinically diverse disorder encompassing Kallmann syndrome (KS) and normosmic CHH (nCHH). Although mutations in numerous genes account for nearly 50% of CHH cases, a significant portion remains genetically uncharacterized. While most mutations follow the traditional Mendelian inheritance patterns, evidence suggests oligogenic interactions between CHH genes, acting as modifier genes to explain variable expressivity and incomplete penetrance associated with certain mutations. In this study, the proband presented with nCHH, while his son exhibited KS. We employed whole-exome sequencing (WES) to investigate the genetic differences between the two, and Sanger sequencing was used to validate the results obtained from WES. Genetic analysis revealed that both the proband and his son harboured a mutation in FGFR1 gene. Notably, an additional rare mutation in PROKR2 gene was exclusively identified in the son, which suggests the cause of the phenotypic difference between KS and nCHH.