RESUMEN
OBJECTIVE: To determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). DESIGN: Polymerase 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. SETTING: Academic 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.