Deafness, Autosomal Dominant 4b

A number sign (#) is used with this entry because of evidence that autosomal dominant nonsyndromic deafness-4B (DFNA4B) is caused by heterozygous mutation in the CEACAM16 gene (614591) on chromosome 19q13.

DFNA4A (600652), another autosomal dominant nonsyndromic deafness phenotype mapping to chromosome 19q13, is caused by mutation in the MYH14 gene (608568).

Description

Autosomal dominant deafness-4B is a form of nonsyndromic progressive sensorineural hearing loss with postlingual onset (summary by Wang et al., 2015)

Clinical Features

Chen et al. (1995) identified a form of autosomal dominant nonsyndromic deafness in members of a large multigenerational family in which fluctuating, though inexorably progressive, sensorineural hearing loss began in the second decade and led to severe to profound impairment by the age of 40 years.

Wang et al. (2015) reported a multigenerational Chinese family with onset of sensorineural hearing loss between 10 and 28 years of age. Only 1 patient had onset at age 3, and this was associated with aminoglycoside exposure. The hearing loss was progressive, resulting in moderately severe to profound deafness. Almost all patients reported high-frequency tinnitus at the onset of hearing loss. None had vestibular impairment.

Inheritance

The transmission pattern of DFNA4B in the family reported by Wang et al. (2015) was consistent with autosomal dominant inheritance.

Mapping

Using polymorphic microsatellite markers in a linkage study of a family segregating autosomal dominant nonsyndromic deafness, Chen et al. (1995) mapped the disorder locus, which they designated DFNA4 (see DNFA4A, 600652), to chromosome 19q13.

Yang et al. (2005) performed complete screening of the MYH14 gene in the American family that originally defined the DFNA4 locus (family 1070 of Chen et al., 1995) but found no mutations in the MYH14 gene (608568). Genotyping of SNPs close to the MYH14 gene excluded it from the candidate region and defined a 19-Mb interval demarcated by D19S414 and SNP rs648298. Yang et al. (2005) concluded that a second gene associated with autosomal dominant nonsyndromic deafness links to the DFNA4 locus, designated here DFNA4B.

Molecular Genetics

In affected members of an American family segregating autosomal dominant deafness mapping to chromosome 19q12-q13.4, originally reported by Chen et al. (1995) (family 1070) and known to be negative for mutation in the MYH14 gene (608568), Zheng et al. (2011) analyzed the candidate gene CEACAM16 and identified heterozygosity for a missense mutation (T140P; 614591.0001). Whole-exome sequencing of the DFNA4 interval excluded other genes as the cause of hearing loss in this family.

In affected members of a Chinese family with DFNA4B, Wang et al. (2015) identified a heterozygous missense mutation in the CEACAM16 gene (G169R; 614591.0002). 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. In vitro functional expression studies in HEK293 cells showed decreased secretion and defective polymerization of the mutant protein compared to wildtype.