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J Med Genet doi:10.1136/jmedgenet-2011-100262
  • Genotype-phenotype correlations
  • Original article

Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes

  1. Thomas B Friedman1
  1. 1Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Rockville, Maryland, USA
  2. 2National Centre of Excellence in Molecular Biology, Punjab University, Lahore, Pakistan
  3. 3Otolaryngology Branch, NIDCD, NIH, Rockville, Maryland, USA
  4. 4Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, USA
  5. 5Division of Pediatric Otolaryngology Head and Neck Surgery, Children's Hospital Research Foundation, Cincinnati, Ohio, USA
  6. 6Division of Ophthalmology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA
  7. 7Department of Otolaryngology, University of Miami, Miami, Florida, USA
  8. 8Department of Pediatrics, Genetics Unit, All India Institute of Medical Sciences, New Delhi, India
  9. 9Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Genetic Medicine, Cambridge, Massachusetts, USA
  10. 10Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  11. 11Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Maryland, USA
  12. 12Allama Iqbal Medical Research Centre, Allama Iqbal Medical College, Lahore, Pakistan
  1. Correspondence to Dr Thomas B Friedman, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, MD 20850, USA; friedman{at}nidcd.nih.gov
  1. Contributors JMS, AJG, ShR, TBF conceived the study and participated in the design and coordination. RB, AMZ, SaR, NA, ZH, MQ, SK, XZL, MM, MG, HLR, ShR contributed to patient enrolment in the study or provided control samples. ACM, AT, JAM, CKZ, KAK, MRM, ETT, WMZ, CCB contributed to clinical evaluations and genetic counselling of the patients. JMS, RB, NA, ZH, MQ carried out the molecular genetic study. JMS, AJG, WMZ, CCB, TBF analysed the data and wrote the manuscript. All authors have read and approved the final manuscript. JMS, TBF are guarantors responsible for this work.

  • Received 14 June 2011
  • Revised 10 August 2011
  • Accepted 15 August 2011
  • Published Online First 22 September 2011

Abstract

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.

Footnotes

  • 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.

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