Phenotypic Spectrum of Idiopathic Hypogonadotropic Hypogonadism Patients With CHD7 Variants From a Large Chinese Cohort

Abstract Purpose Idiopathic hypogonadotropic hypogonadism (IHH) and CHARGE (C, coloboma; H, heart abnormalities; A, choanal atresia, R, retardation of growth and/or development; G, gonadal defects; E, ear deformities and deafness) syndrome are 2 distinct developmental disorders sharing features of hypogonadism and/or impaired olfaction. CHD7 variants contribute to >60% CHARGE syndrome and ~10% IHH patients. A variety of extended CHARGE-like features are frequently reported in CHARGE patients harboring CHD7 variants. In this study, we aimed to systematically analyze the diagnostic CHARGE features and the extended CHARGE-like features in patients with IHH with CHD7 variants. Methods Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 177 IHH probands. Detailed phenotyping was performed in the IHH patients harboring CHD7 variants and their available family members. Results CHD7 RSVs were identified in 10.2% (18/177) of the IHH probands. Two diagnostic CHARGE features, hearing loss and ear deformities, were significantly enriched in patients with CHD7 variants. Furthermore, CHD7 variants were significantly associated with a panel of extended CHARGE-like phenotypes, including mild ocular defects, dyspepsia/gastroesophageal reflux disease and skeletal defects. We also developed a predictive model for prioritizing CHD7 genetic testing in IHH patients. Conclusion CHD7 variants rarely cause isolated IHH. Surveillance of symptoms in CHARGE syndrome-affected organs will facilitate the proper treatment for these patients. Certain clinical features can be useful for prioritizing CHD7 genetic screening.