Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Inactivating mutations in chromodomain helicase DNA binding protein 7 ( CHD7 ) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings ( i ) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, ( ii ) reiterate the emerging genetic complexity of this family of IGD disorders, and ( iii ) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems. Significance Inactivating mutations in the chromodomain helicase DNA binding protein 7 ( CHD7 ) gene causes a severe developmental disorder known as CHARGE syndrome. Recently, several missense mutations in CHD7 have been reported in isolated gonadotropin-releasing hormone (GnRH) -deficiency (IGD) patients who lack full CHARGE features. However, the precise functional consequence of these IGD-associated missense mutations on the activity of CHD7 protein is not known. This study confirms the predominance of missense CHD7 alleles in 5% of IGD patients and provides, to our knowledge, first experimental evidence that functionally compromised CHD7 missense alleles contribute to the pathogenesis of both the anosmic and normosmic forms of IGD. These results imply a preferential sensitivity for CHD7 dysfunction