Deafness, Autosomal Dominant 22

A number sign (#) is used with this entry because of evidence that autosomal dominant nonsyndromic deafness-22 (DFNA22) is caused by heterozygous mutation in the myosin VI gene (MYO6; 600970) on chromosome 6q14.

Clinical Features

Melchionda et al. (2001) studied a large Italian kindred in which many members were affected with autosomal dominant nonsyndromic sensorineural hearing loss. Hearing loss was progressive and postlingual, with onset during childhood (8 to 10 years of age at onset of symptoms; 6 to 8 years of age at onset of first audiometric abnormalities). By the age of approximately 50 years, affected individuals invariably had profound sensorineural deafness. Vestibular and/or visual involvement was excluded in all affected individuals.

Sanggaard et al. (2008) investigated a large Danish family with 18 affected members segregating nonsyndromic autosomal dominant sensorineural hearing loss. By history, hearing loss was typically noticeable by school age and hearing aids were required in adulthood. No subjective vestibular dysfunction was noted in affected family members; the proband did not have hypertrophic cardiomyopathy or retinal degeneration.

Hilgert et al. (2008) examined affected individuals from 2 Belgian families segregating autosomal dominant deafness in which the hearing loss started during the third decade for most individuals and showed slight progression. The 19 affected members of 'family 1' had rather flat audiograms affecting all frequencies to a similar degree, and hearing loss was mild at onset, evolving to moderate to severe by 50 years of age. The 11 affected members of 'family 2' had hearing loss mainly affecting the mid-frequencies and ranging from mild to severe.

Mapping

By linkage analysis in an Italian family segregating a form of autosomal dominant deafness, Melchionda et al. (2001) mapped the disorder in this family to chromosome 6q13, a region to which the myosin VI gene maps. The mouse Myo6 gene maps to a homologous region of chromosome 9. Mutations in the mouse Myo6 gene are associated with deafness and vestibular dysfunction in the Snell's waltzer (sv) mouse.

In 2 Belgian families segregating autosomal dominant deafness, Hilgert et al. (2008) found linkage to the DNFA22 locus on chromosome 6q, with a maximum 2-point lod score of 6.06 for family 1 and a maximum multipoint lod score of 5.4 for family 2. Haplotype analysis defined a 2.37-cM region between markers D6S456 and D6S460 in family 1; in family 2, a 9.08-cM region between markers D6S1557 and D6S1652 was defined that completely encompassed the linked region of family 1.

Molecular Genetics

In a family with DFNA linked to chromosome 6q13, Melchionda et al. (2001) identified mutations in the MYO6 gene (600970.0001).

In affected members of a kindred in which autosomal dominant sensorineural deafness cosegregated with familial hypertrophic cardiomyopathy, Mohiddin et al. (2004) identified a his246-to-arg mutation in the MYO6 gene (H246R; 600970.0005).

In affected members of a large Danish family with autosomal dominant deafness mapping to chromosome 6p12.1-q16.1, Sanggaard et al. (2008) identified heterozygosity for a nonsense mutation in the MYO6 gene (600970.0006).

Hilgert et al. (2008) analyzed the MYO6 gene in 2 Belgian families with autosomal dominant deafness mapping to the DFNA22 locus and identified a splice site mutation in family 2 that segregated with disease (600970.0007). No mutation was identified in family 1, although quantitative real-time PCR revealed 1.5- to 1.8-fold overexpression of MYO6 in patients compared to controls. After exclusion of gene duplication, the authors suggested that most likely the overexpression involved a mutation in an as yet unidentified regulatory region of the MYO6 gene.