Deafness, Autosomal Recessive 25

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-25 (DFNB25) is caused by homozygous mutation in the GRXCR1 gene (613283) on chromosome 4p13.

Clinical Features

Schraders et al. (2010) reported 3 sibs from a nonconsanguineous Dutch family, 1 sporadic Dutch patient, and affected members of 2 consanguineous Pakistani families with DFNB25. The 4 Dutch patients exhibited normal development of speech despite the very early onset of hearing loss, and the hearing loss in the 3 Dutch sibs was progressive. Two of the sibs had symptoms of vestibular dysfunction at 2 years and 4 years of age, respectively, but normal motor function, suggesting that the vestibular dysfunction was not congenital. Affected individuals in the Pakistani families did not develop speech, suggesting a more severe hearing loss in the critical period than in the Dutch families. Audiograms in the Pakistani patients showed a flat, slightly U-shaped or slightly downsloping pattern that was similar to that seen in the Dutch sibs, and their hearing loss was moderate to severe. There was no evidence for progression of disease or vestibular dysfunction in the Pakistani families.

Mapping

Schraders et al. (2010) performed homozygosity mapping in a large series of 59 familial and 23 sporadic Dutch patients with nonsyndromic hearing impairment (NSHI) and identified an overlapping homozygous region on chromosome 4p13 shared by 1 nonconsanguineous Dutch family and 1 sporadic patient, located within a deafness locus designated DFNB25. Linkage analysis in 10 consanguineous Pakistani families showed linkage or suggestive linkage to the region. A 0.9-Mb critical region defined by the nonconsanguineous Dutch family contained exon 1 of the ATP8A1 gene (609542) and the complete GRXCR1 gene (613283) as well as 4 uncharacterized expressed sequence tags.

Molecular Genetics

In a nonconsanguineous Dutch family and a sporadic Dutch patient with nonsyndromic hearing impairment mapping to 4p13 and 10 consanguineous Pakistani families with NSHI, Schraders et al. (2010) analyzed exon 1 of the ATP8A1 gene and all exons of the GRXCR1 gene. No variants were found in ATP8A1, but 4 different homozygous mutations in GRXCR1 were identified in the 2 Dutch families and 2 of the Pakistani families, respectively (613283.0001-613283.0004), that cosegregated with disease and were not found in 180 Dutch or 240 Pakistani controls.