CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct

AbstractEnlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants inSLC26A4. However, in European –Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles ofSLC26A4. We tested for the presence of variants inCHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles ofSLC26A4. In two families, NM_017780.4: c.3553A  >  G [p.(Met1185Val)] and c.5390G >  C [p.(Gly1797Ala)] were detected as monoallelicCHD7 variants in patients with EVA. At least one subject from each family had additional signs or potential signs of CHARGE syndrome but did not meet diagnostic criteria for CHARGE. In silico modeling of these two missense substitutions predicted detrimental effects upon CHD7 protein structure. Consistent with a role of CHD7 in this tissue,Chd7 transcript and protein were detected in all epithelial cells of the endolymphatic duct and sac of the developing mouse inner ear. These results suggest that someCHD7 variants can cause nonsyndromic hearing loss and EVA.CHD7 should be included in DNA sequence analyses to detect pathogenic variants in EVA patients.Chd7 expression and mutant phenotype data in mice suggest that CHD7 contributes to the formation or function of the...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research