Deafness, Autosomal Dominant 28

A number sign (#) is used with this entry because DFNA28 is caused by heterozygous mutation in the GRHL2 gene (608576) on chromosome 8q22.

Clinical Features

Peters et al. (2002) reported a large American family in which 11 members spanning 5 generations were affected with sensorineural hearing loss. Affected individuals showed a mild to moderate hearing loss across most frequencies that progressed to severe loss in the higher frequencies by the fifth decade. Age at onset varied, with the earliest case documented at 7 years of age.

Vona et al. (2013) studied a large 5-generation family segregating autosomal dominant postlingual hearing loss with a highly variable age of onset and progression. The proband was a man who developed bilateral progressive hearing loss at age 32 years. Hearing loss in family members with detailed clinical examination was characterized as bilateral, progressive, and usually beginning in the fifth decade of life; the youngest documented age of diagnosis was 32 years and the oldest was 65 years. However, more distantly related individuals without detailed clinical records reported postlingual childhood onset of hearing loss. Affected family members who were examined showed mild (20-40 dB) to moderate (40-55 dB) sensorineural hearing loss in the fourth to seventh decade of life that progressed to moderately severe (55-70 dB) levels in higher frequencies by the seventh and eighth decades.

Molecular Genetics

In affected members of the American family with DFNA28, Peters et al. (2002) identified a heterozygous frameshift mutation in the GRHL2 gene (608576.0001).

In the proband of a large 5-generation family segregating autosomal dominant postlingual hearing loss with a highly variable age of onset and progression, who was negative for mutation in the GJB2 gene (121011) and for copy number variation, Vona et al. (2013) screened 80 known deafness-associated genes and identified a heterozygous splice site mutation in the GRHL2 gene (608576.0002) that segregated with disease in the family. Analysis of 24 additional GJB2-negative hearing loss patients revealed no further mutations in GRHL2.