F1000Prime Recommendation of [Quaynor SD et al, Mol Cell Endocrinol. 2016 Dec 05; 437: 86-96]

The paper describes the genetic analysis of 48 hypogonadic (normosmic hypogonadotropic hypogonadism [nHH]/Kallmann syndrome [KS]) patients by targeted next-generation sequencing (NGS) of more than 250 genes involved in hypothalamic, pituitary, and/or olfactory pathways; other genes were included in the analysis because they were involved in chromosome rearrangements. Central hypogonadotropic hypogonadism often shows complex phenotypes and a quite clear multigenic component to its etiology; therefore, the use of the NGS technique offers great advantages. The results describe the identification of 18 new candidate genes for nHH/KS and two novel mutations for FGFR1, one of the most frequent genes mutated in the disease. Of interest, similarly to the more than 20 genes already found causative of nHH/KS, the new genes described are coding for factors involved in different biological/physiological functions: from cell migration, axonal extension and cell differentiation to cell cycle, transcription and chromatin regulation; from signal transduction to intracellular signaling and transcription. This new finding is clearly indicative of the complexity of such a disease and of the multigenic organization of the development and function of the mammalian reproductive axis.