Usher Syndrome, Type Ic

A number sign (#) is used with this entry because Usher syndrome type IC is caused by homozygous or compound heterozygous mutation in the gene encoding harmonin (605242) on chromosome 11p15.

Description

Usher syndrome type I is an autosomal recessive condition characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa (usually evident within the first decade), and constant vestibular dysfunction. Type I is distinguished from type II (276901) on the basis of severity of hearing loss and the extent of vestibular involvement. Type I patients are profoundly deaf, whereas type II patients are 'hard of hearing.' Vestibular function is defective in type I patients, whereas type II patients have normal vestibular function (Moller et al., 1989). Patients with type III (USH3; 276902) have progressive hearing loss.

For a discussion of genetic heterogeneity of Usher syndrome type I, see USH1 (276900).

Clinical Features

Kloepfer et al. (1966) identified 537 persons with hearing loss in a French-Acadian ('Cajun') group in Louisiana. Of the 468 living persons with hearing loss, at least 158 or about 30% were known to have retinitis pigmentosa and cataract.

Usher syndrome in French-Acadians is predominantly type I, although some type II cases have been identified (Smith et al., 1992).

Saihan et al. (2011) studied a 42-year-old woman and her 40-year-old brother from a Caucasian British family who at 4 years of age were diagnosed with severe hearing loss requiring hearing aids, and who also developed visual field loss and night blindness in the third and fourth decades of life, respectively. Language acquisition and speech development were normal, and there was no history of delay in motor milestones, consistent with normal vestibular function in infancy. Ophthalmic examination revealed that both sibs had sector retinitis pigmentosa restricted to the inferior and nasal retina, and fundus autofluorescence imaging showed a clear demarcation between normal and abnormal areas of retina, which corresponded to areas of reduced sensitivity on fine matrix mapping and loss of visual field.

Mapping

In the Acadian families of Louisiana, Smith et al. (1992) demonstrated that Usher syndrome was linked to D11S419 (maximum lod = 4.20 at theta = 0.0), which is situated on 11p. A homologous region on mouse chromosome 7 is the site of a recessive deaf mutant 'twister' (twt), a disorder possibly homologous to Usher syndrome.

Keats et al. (1994) mapped the USH1C gene to a region of 11p15.1 by tight linkage to microsatellite markers. In addition, linkage disequilibrium was observed. Fantes et al. (1995) constructed an integrated map of this region, including the markers tightly linked to USH1C.

Molecular Genetics

In patients with Usher syndrome IC, Verpy et al. (2000) found a splice site mutation (605242.0001), a frameshift mutation (605242.0002), and the expansion of an intronic variable number of tandem repeats (VNTRs) (605242.0003). Verpy et al. (2000) proposed that the USH1C gene also underlies the form of nonsyndromic autosomal recessive neurosensory deafness designated DFNB18 (602092), which maps to the same region of 11p.

Bitner-Glindzicz et al. (2000) identified the USH1C gene and detected 2 different homozygous mutations in exon 3, one in an Acadian family (605242.0004) and the other in a Pakistani family (605242.0002) with Usher syndrome type IC. Additionally, they identified a contiguous gene deletion syndrome (606528) that included part of the ABCC8 (600509) and USH1C genes in 2 consanguineous families.

In an extensive genetic study of 9 Usher syndrome genes in 172 patients with Usher syndrome due to various genetic defects, Le Quesne Stabej et al. (2012) found that mutations in the USH1C gene were the second most common defect, accounting for 14.9% of families. Four families carried a splice site mutation (495+1G-A; 605242.0006), and haplotype analysis indicated a founder effect. Mutations in the MYO7A gene (276903) were the most common in the cohort, accounting for 53.2% of families.

In 2 sibs from a Caucasian British family who were diagnosed with hearing loss at 4 years of age and who developed retinitis pigmentosa of the 'sector' type in the third and fourth decades of life, respectively, Saihan et al. (2011) identified compound heterozygosity for a missense mutation (R103H; 605242.0011) and a splice site mutation (605242.0012) in the USH1C gene. Both sibs were negative for pathogenic changes in 7 other Usher-associated genes. Their unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 866 control chromosomes. Saihan et al. (2011) noted that both the retinal and the audiovestibular phenotypes in the sibs were much milder than those previously reported in cases of USH1C-related nonsyndromic hearing loss or Usher syndrome type I.

Using a combination of whole-genome SNP analysis as well as whole-exome sequencing in 2 Israeli families of Yemenite Jewish descent with retinitis pigmentosa, Khateb et al. (2012) identified a homozygous 1-bp deletion in the USH1C gene (1220delG; 605242.0013) that was confirmed by Sanger sequencing and cosegregated fully with the phenotype in both families. The mutation was part of a shared homozygous haplotype of 27 SNPs shared by the probands from the 2 families, indicating a founder mutation; screening for the 1220delG mutation in 119 ethnically matched controls revealed 1 heterozygous individual, for a carrier frequency of 0.008 in the Israeli Yemenite Jewish population. Screening 35 unrelated Yemenite Jewish patients with retinal degeneration identified 6 additional RP patients who were homozygous for the 1220delG mutation. Audiometric testing in 10 of the mutation-positive individuals revealed that 4 had mild to severe symmetric hearing impairment; the ages of the patients with deafness ranged from 38 to 72 years, whereas those of the patients with normal hearing ranged from 13 to 40 years. Khateb et al. (2012) stated that this was the first report of a mutation in a known USH1 gene causing late-onset rather than congenital sensorineural hearing loss, and noted that the mutation accounted for 23% of RP among Yemenite Jewish patients in their cohort.

History

In the French-Acadian ('Cajun') population of southwestern Louisiana where Usher syndrome is frequent (Kloepfer et al., 1966), Daiger et al. (1987) and Pelias et al. (1988) found a suggestion of linkage to GC (139200) on 4q (maximum lod score = 1.41 at theta = 0.17). In the same large Louisiana kindred, Smith et al. (1988, 1989) excluded the Usher syndrome locus from a large part of chromosome 4 by multipoint linkage analysis. Notably, a 17-cM region around the GC locus was excluded by reason of a lod score less than -2.0. Bonneau et al. (1990) also excluded linkage to GC.