The role of CHD7 and the newly identified WDR11 gene in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome

Mutations in the chromodomain helicase DNA binding protein-7 (CHD7) cause CHARGE syndrome, which includes eye coloboma, heart malformations, atresia of the choanae, retardation of growth/development, genital anomalies, and ear abnormalities. CHARGE syndrome is usually sporadic, but is also autosomal dominant. CHD7 encodes a large protein that participates in chromatin remodeling and transcription. Findings from studies of mouse models employing ENU-mutagenesis or gene-trap methods recapitulate human CHARGE syndrome. CHARGE patients may manifest anosmia and/or hypogonadism, features that overlap with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS). Similarly, IHH/KS patients may also display partial CHARGE features. Therefore, it has been hypothesized that IHH/KS represents a milder allelic variant of CHARGE syndrome, which has been supported by the identification of heterozygous CHD7 mutations in both normosmic IHH and KS. Developmental expression within the hypothalamus and the presence of human mutations indicate that CHD7 has an important role in puberty and reproduction. In addition, WDR11 was recently identified by positional cloning; and mutations in were identified in IHH/KS patients, suggesting a role for this gene in normal puberty.

► Mutations in the CHD7 gene cause CHARGE syndrome, a multisystem genetic disorder.
► CHARGE syndrome and Kallmann syndrome (KS) share overlapping phenotypes.
► CHD7 mutations were identified in KS and normosmic IHH patients without full CHARGE.
► Evidence indicates that CHARGE syndrome, KS, and normosmic IHH are allelic variants.
► WDR11 was identified as a new IHH/KS gene by positional cloning techniques.