Deafness, Autosomal Dominant 37

A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-37 (DFNA37) is caused by heterozygous mutation in the COL11A1 gene (120280) on chromosome 1p21. One such family has been reported.

Description

DFNA37 is an autosomal dominant form of early-onset postlingual progressive hearing impairment (Booth et al., 2019).

Clinical Features

Booth et al. (2019) reported a large 4-generation family of European descent with postlingual, slowly progressive sensorineural hearing loss. Pure-tone audiometric evaluation showed mild to moderate hearing loss, although the finding of a significant threshold intercept at age 0 years at all frequencies except 8 kHz suggested the presence of a substantial congenital component (of 12 to 23 dB). The mean audiogram configuration developed from U-shaped to flat with advancing age up to about 40 years; at more advanced ages it remained flat or became very gently downsloping. Detailed analysis of the progression was expressed in dB per year, designated annual threshold deterioration (ATD).

Inheritance

The transmission pattern of DFNA37 in the family reported by Booth et al. (2019) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a family with DFNA37, Booth et al. (2019) identified a heterozygous splice site mutation in the COL11A1 gene (120280.0013). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Using a minigene construct to express the mutation in cell lines, the authors showed that mutation resulted in the skipping of exon 5, causing an in-frame deletion and a peptide lacking residues 218 to 260 in the N-terminal propeptide. The mutation was predicted to affect all 5 transcripts of the gene, but possibly had a 'leaky' effect.