New intronic Fibroblast Growth Factor Receptor 1 (FGFR1) mutation leading to disrupted splicing and Kallmann syndrome

Abstract Congenital hypogonadotropic hypogonadism (CHH), which can present with a defective sense of smell (Kallmann syndrome, KS), is a clinically and genetically heterogeneous disorder. Over 31 genes have been associated with CHH, but most of the patients still lack a molecular genetic diagnosis. Some cases may be explained by mutations that disrupt the splicing of already established CHH genes but that are unrecognized either because they are located deep in introns or are not predicted to disrupt splicing. Here we identified a patient with a previously unreported Fibroblast Growth Factor Receptor 1 (FGFR1) mutation, c.1664-9T>G, that leads to the skipping of exon 13 of FGFR1. Notably, the mutation was not predicted to cause a significant alteration in the splicing motif but in vitro analysis confirmed the pathogenicity of the mutation. Our results thus reveal a new splicing-affecting mutation in FGFR1 and suggest that all new sequence variants located close to exon/intron boundaries should be experimentally investigated for pathogenicity, rather than relying solely on computer prediction programs.