Context: Congenital hypogonadotropic hypogonadism (CHH) and CHARGE syndrome are clinically and genetically overlapping syndromes, with mutations in the CHD7 gene presenting in both disorders. However systematic evaluation of CHARGE features in CHD7-positive CHH patients is seldom performed.
Objective: This study aims to systematically evaluate CHARGE features in CHD7-positive patients and explore the phenotype-genotype correlation.
Design: Whole exome sequencing was performed on 130 CHH probands to identify mutations in 24 CHH genes, including CHD7. Putative mutations were defined as rare sequence variants (RSVs, minor allele frequency <1%) that were either protein-truncating variants (PTVs) or missense variants predicted to be deleterious by SIFT and/or PolyPhen2. Missense mutations were also evaluated using Bergman criteria, integrating computational algorithms, population and segregation data (Bergman, Human Mutation, 2012). CHD7-positive CHH patients were evaluated for CHARGE features.
Results: We identified 16 CHH patients harboring heterozygous mutations (two PTVs and 14 missense), of whom 14 were available for re-evaluation. After detailed phenotyping, three probands (one PTV and two missense) were re-classified as CHARGE syndrome. Four probands with missense mutations present additional CHARGE features, while the remaining seven probands exhibit no additional CHARGE feature (one PTV and six missense). Both the missense mutations underlying CHARGE syndrome were categorized as pathogenic using Bergman criteria, while the other missense mutations were classified as either benign or of unknown significance. Of note, 3/4 CHH patients with additional CHARGE features also had mutations in other CHH genes, contributing to the variable expressivity.
Conclusions: 50% of CHD7-positive CHH patients exhibit additional CHARGE features, with 21% meeting the clinical diagnosis of CHARGE syndrome. While the Bergman criteria accurately predict the most severe mutations resulting in CHARGE syndrome, it is unable to distinguish isolated CHH from CHH with additional CHARGE features. The results of this study have diagnostic and genetic counseling implications for CHD7-positive CHH patients.
20 - 23 May 2017
European Society of Endocrinology