Usher syndrome type I is an autosomal recessive disorder characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa, and constant vestibular dysfunction. Gerber et al. (1996) suggested the existence of a novel form of Usher ... Usher syndrome type I is an autosomal recessive disorder characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa, and constant vestibular dysfunction. Gerber et al. (1996) suggested the existence of a novel form of Usher syndrome type I from the fact that the 3 previously reported loci were excluded by linkage studies in 2 families of Moroccan and Pakistani ancestry. Wayne et al. (1996) reported that a first-cousin union in a family of Pakistani origin produced 4 children with clinical signs of Usher syndrome, including profound prelingual auditory impairment of sensorineural type, congenital vestibular dysfunction, and progressive pigmentary retinopathy.
Nonsyndromic DFNB12 deafness is associated with CDH23 missense mutations that are presumed to be hypomorphic alleles with sufficient residual activity for retinal and vestibular function, but not for auditory cochlear function. In contrast, homozygous nonsense, frameshift, splice site ... Nonsyndromic DFNB12 deafness is associated with CDH23 missense mutations that are presumed to be hypomorphic alleles with sufficient residual activity for retinal and vestibular function, but not for auditory cochlear function. In contrast, homozygous nonsense, frameshift, splice site and some missense mutations of CDH23, or a combination of these USH1D alleles in a compound heterozygote, cause USH1D. Schultz et al. (2011) identified 12 different homozygous CDH23 missense mutations, including 8 novel mutations, in 13 families with DFNB12. All were missense, except 1 in-frame deletion. Ten different homozygous mutations were found in 14 families and 1 singleton with USH1D. These latter mutations were mostly nonsense, frameshift, or splice site mutations, but there was 1 in-frame deletion and 2 missense mutations. Affected individuals in 3 additional families were found to carry compound heterozygous mutations in the CDH23 gene, with the different alleles being associated with either DFNB12 or USH1D. Based on the phenotypes within families, the results indicated that USH1D occurs only when there are 2 USH1D alleles in trans. In contrast, when there is a DFNB12 allele in trans with a USH1D allele, the phenotype is DFNB12. The findings indicated that a DFNB12 allele is phenotypically dominant to a USH1D allele, and can preserve normal retinal and vestibular function even in the presence of a USH1D allele. Schultz et al. (2011) noted the implications for genetic counseling.
Bolz et al. (2001) identified mutations in the CDH23 gene (605516) in a Cuban family and a German patient with USH1D. Di Palma et al. (2001) demonstrated that mutations in the ... - Usher Syndrome Type ID Bolz et al. (2001) identified mutations in the CDH23 gene (605516) in a Cuban family and a German patient with USH1D. Di Palma et al. (2001) demonstrated that mutations in the mouse Cdh23 gene are responsible for the 'waltzer' mutation, thus establishing it as a model for USH1D. - Autosomal Recessive Deafness 12 Bork et al. (2001) showed that USH1D and DFNB12 are allelic disorders. - Usher Syndrome Type ID/F, CDH23/PCDH15 Digenic Following the demonstration that mice heterozygous for mutations in both Cdh23 and Pcdh15 (605514) manifest a progressive hearing loss phenotype, Zheng et al. (2005) carried out mutation screening for CDH23 and PCDH15 mutations in 76 probands with a diagnosis of USH1. They found 3 probands who carried heterozygous mutations in both CDH23 and PCDH15. All had profound congenital nonprogressive deafness, vestibular dysfunction, and retinitis pigmentosa. The first proband carried a 3-bp in-frame deletion in PCDH15 (5601delAAC; 605514.0005) that had been identified in patients with USH1F (602083) and a single-basepair deletion in CDH23 (193delC; 605516.0011) that had been identified in patients with USH1D. The second proband was heterozygous for a 16delT mutation in PCDH15 (605514.0008) and a missense mutation in CDH23 (R3189W; 605516.0012). The third proband was heterozygous for the same in-frame deletion in PCDH15 as the first proband, and homozygous for a previously identified missense mutation in CDH23 (T1209A; 605516.0013). The CDH23 T1209A mutation had been identified in USH1D patients, and the authors suggested that the more severe phenotype in this patient was due to a modifier effect of the PCDH15 5601delAAC mutation. (The CDH23 T1209A mutation was later reclassified as a variant of unknown function.) All mutations were considered pathologic because of their location in functionally important and evolutionarily conserved domains and their absence in 100 unrelated controls.