Background Recessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth.
Methods and results To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele.
Conclusions One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome.
Accession numbers The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.
- genotype–phenotype correlation
- Usher syndrome
- molecular genetics
- genetic screening/counselling
- clinical genetics
- other neurology
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Funding This study was supported by NIDCD intramural research funds DC000039-14, DC000060-10, and DC000064-10 to TBF, AJG and CCB, respectively, and the Intramural Research Program of the National Eye Institute, and support by the Higher Education Commission and Ministry of Science and Technology and the International Center for Genetic Engineering and Biotechnology, Trieste, Italy under project CRP/PAK08-01 Contract no. 08/009 to ShR.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Combined Neuroscience Institutional Review Board (IRB) at the National Institutes of Health, Bethesda, Maryland, USA, the IRB at the National Centre of Excellence in Molecular Biology, Lahore, Pakistan, or the IRB at the All India Institute of Medical Sciences, New Delhi, India.
Provenance and peer review Not commissioned; externally peer reviewed.