Deafness, Autosomal Recessive 30

A number sign (#) is used with this entry because of the finding that this form of autosomal recessive deafness, DFNB30, is caused by mutations in the myosin IIIA gene (MYO3A; 606808).

Clinical Features

Walsh et al. (2002) studied a family that traced its ancestry to the Jewish community of Mosul, Iraq. This community dated to 586 B.C. and was highly endogamous, with considerable emigration but little immigration, for more than 2,500 years. Most remaining Jewish residents of Mosul, including this family, migrated to Israel in 1950-1951. Three generations of the family had experienced bilateral progressive hearing loss, which first affected the high frequencies. Hearing loss began in the second decade, and by age 50, was severe in high and middle frequencies and moderate at low frequencies. Vision and balance of all affected individuals were normal. Inheritance of deafness in this family was likely recessive with age-dependent penetrance, although dominant inheritance could not be excluded.

Mapping

By genomewide linkage analysis, Walsh et al. (2002) identified a locus for DFNB30 on chromosome 10p in 23 members of an Israeli family that can be traced to the Jewish community of Mosul, Iraq. They found evidence of linkage to an interval between D10S1749 and D10S1654 with a lod score of 4.3. Fine mapping by SNPs revealed no subregion homozygous in all affected relatives, leading to the conclusion that multiple alleles (or even multiple genes) were likely to be responsible for deafness in this family. The critical region for the myosin IIIA gene (606808) seemed to be an excellent candidate for DFNB30, because 4 other myosins had been associated with hearing loss: MYO7A (276903), MYH9 (160775), MYO6 (600970), and MYO15A (602666).

Molecular Genetics

Walsh et al. (2002) determined that DFNB30 is caused by mutations in the MYO3A gene (606808).

Genotype/Phenotype Correlations

Three mutations in MYO3A fully explained the hearing loss in the family described by Walsh et al. (2002), in that there was complete concordance of MYO3A genotypes and hearing loss. All homozygotes and compound heterozygotes were deaf; all simple heterozygotes were carriers with normal hearing. Variability in age of onset of hearing loss could be explained. Between age 25 and 50 years, hearing across all frequencies was significantly poorer among individuals homozygous for the nonsense mutation than among individuals heterozygous for the nonsense mutation in combination with either of the splice mutations. Hearing loss was equally severe in all affected individuals by the sixth decade.