F1000Prime Recommendation of [Quaynor SD et al., Fertil Steril 2011, 96(6):1424-1430.e6]

Kallmann Syndrome (KS) is a rare genetic disease defined by the association of infertility (hypogonadotropic hypogonadism), and anosmia. When the disease is associated with normal sense of smell, it is classified as normosmic idiopathic central hypogonadism (IHH). The rare loci underlying IHH/KS include at least 17 single genes; however, recent evidence suggests a digenic or oligogenic pathogenesis. In this paper, the authors evaluated the prevalence of digenic mutations in 48 patients with IHH and KS by molecular analysis of DNA, considering the most common 13 genes found to be mutated in these diseases. Using an original experimental design, they report that the overall prevalence of digenic gene mutations was only 12.5% of the IHH/KS patients included in the study, indicating that monogenic mutations account for most cases of IHH/KS. Nevertheless, the study of the few cases of digenic or oligogenic mutations may be useful for suggesting which genes could interact with each other and could therefore be involved in the same developmental pathway by synergistic heterozygosity. These data may be important for a better understanding of the genetic mechanisms involved in the development of the neuroendocrine control of reproduction and for the identification of new candidate genes by computational prediction analysis.