Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Area of Science:

• Genetics
• Developmental Biology
• Endocrinology

Background:

• Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome.
• Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a feature of CHARGE syndrome, and CHD7 variants have been reported in IGD patients.
• The role of CHD7 in Kallmann syndrome (KS) and normosmic IGD, particularly in the absence of full CHARGE syndrome, requires further investigation.

Purpose of the Study:

• To investigate the contribution of rare CHD7 alleles to the genetic etiology of KS and normosmic IGD in patients without full CHARGE syndrome.
• To determine the functional impact of identified CHD7 variants in a relevant model system.
• To explore the genetic complexity of IGD by examining co-occurrence of CHD7 mutations with other known IGD genes.

Main Methods:

• Sequencing of the CHD7 gene in 783 well-phenotyped IGD patients.
• Functional analysis of CHD7 alleles in zebrafish using a surrogate otolith assay.
• Analysis of mutation co-occurrence in familial cases.

Main Results:

• Nonsynonymous rare sequence variants in CHD7 were identified in 5.2% of the IGD cohort.
• Functional studies revealed that 75% of IGD-associated CHD7 alleles were deleterious, impacting KS and normosmic IGD.
• Pathogenic mutations in CHD7 coexisted with mutations in other IGD genes in two families.

Conclusions:

• Rare, deleterious CHD7 alleles contribute to the mutational burden in patients with KS and normosmic IGD, even without full CHARGE syndrome.
• CHD7 plays a specific role in the development of GnRH neurons.
• The genetic architecture of IGD is complex, involving multiple genes and potentially synergistic effects.