Identification of HESX1 mutations in Kallmann syndrome

Abstract

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.