Identification of HESX1 mutations in Kallmann syndrome

ObjectiveTo determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS).DesignPolymerase chain reaction-based DNA sequencing was performed on 217 well-characterized IHH/KS patients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal Ω.SettingAcademic medical center.Patient(s)Two hundred seventeen patients with IHH/KS and 192 controls.Intervention(s)Deoxyribonucleic acid was extracted from patients and controls; genotype/phenotype comparisons were made.Main Outcome Measure(s)Deoxyribonucleic acid sequence of HESX1, SIFT analysis, and ortholog alignment.Result(s)Two novel heterozygous missense mutations (p.H42Y and p.V75L) and previously reported heterozygous missense mutation p.Q6H in HESX1 were identified in 3 of 217 patients (1.4%). All were males with KS. Both p.Q6H and p.H42Y were predicted to be deleterious by SIFT, whereas p.V75L was conserved in 8 of 9 species. No other IHH/KS gene mutations were present.Conclusion(s)HESX1 mutations may cause KS in addition to more severe phenotypes. Our findings expand the phenotypic spectrum of HESX1 mutations in humans, thereby broadening its role in development.