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CHARGE syndrome is a rare genetic disease characterized by numerous congenital abnormalities, mainly caused by de novo alterations of the CHD7 gene. It encodes a chromodomain protein, involved in the ATP-dependent remodeling of chromatin. The vast majority of CHD7 alterations consists in null alleles like deletions, nonsense substitutions or frameshift-causing variations. The aim of this study was to develop a biological test of CHD7 protein, to study the impact upon protein functionality of rare allelic variants in the CHD7 gene that elicits changes in the amino acid sequence. Using an expression vector encoding CHD7, three amino acid substitutions and one five-amino acid insertion were generated via site-directed mutagenesis. Then CHD7 proteins, either wild-type (WT) or variants, were overexpressed in HeLa cell line. Protein expression was highlighted by western blot and immunofluorescence. We then used real-time RT-PCR to study CHD7 functionality by evaluating the transcript amounts of five genes whose expression is regulated by CHD7 according to the literature. These reporter genes are 45S rDNA, SOX4, SOX10, ID2, and MYRF. We observed that, upon WT-CHD7 expression, the reporter gene transcriptions were downregulated, whereas the four variant alleles of CHD7 had no impact. This suggests that these alleles are not polymorphisms because the variant proteins appeared nonfunctional. Therefore, these variations can be considered as disease-causing of CHARGE syndrome.

A functional assay to study the pathogenicity of CHD7 protein variants encountered in CHARGE syndrome patients