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

Abstract

Enlargement 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 in SLC26A4. However, in European–Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles of SLC26A4. We tested for the presence of variants in CHD7, 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 of SLC26A4. In two families, NM_017780.4: c.3553A > G [p.(Met1185Val)] and c.5390G > C [p.(Gly1797Ala)] were detected as monoallelic CHD7 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 some CHD7 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 endolymphatic sac and duct.

Detailed analysis of inner ear malformations in CHARGE syndrome patients – correlation with audiological results and proposal for computed tomography scans evaluation methodology

“…More than 1000 mutation variants that can cause CHARGE syndrome have been identified. 6 , 8 , 9 , 10 , 11 , 12 In this study, six analyzed patients underwent genetic testing confirming the gene mutations. Four were not analyzed genetically due to parents' no agreement with these tests but presented typical specific and recognizable patterns of CHARGE anomalies.…”

CHD7 Disorder—Not CHARGE Syndrome—Presenting as Isolated Cochleovestibular Dysfunction

“…Temporal bone abnormalities include cochlear hypoplasia and the absence or underdevelopment of semicircular canals. Only recently, CHD7 variant alleles have also been implicated in the etiology of enlarged vestibular aqueduct [EVA] and associated sensorineural hearing loss [19]. The authors advised evaluating potential CHARGE manifestations in individuals with EVA, especially in cases lacking SLC26A4 pathogenic variants.…”