[Usher type I syndrome in children: genotype/phenotype correlation and cochlear implant benefits]. / Syndrome de Usher de type I chez l'enfant: corrlation génotype/phénotype et bénéfice de l'implant cochléaire.

OBJECTIVE: To assess the benefit of cochlear implant in children presenting an Usher type 1 syndrome (speech understanding, speech production intelligibility, academic performance) and to search any correlation between the phenotype and the genotype in this population. MATERIALS AND METHODS: Retrospective case series analysis about 13 implanted Usher type I children. Cochlear implantation was performed from 1995 to 2005. Our population was divided in three groups: group 1 (implantation between 1 and 3 years of age); group 2 (implantation between 4 and 7 years of age) and group 3 (implantation between 14 and 17 years of age). Postoperative speech perception, speech production intelligibility and education settings were evaluated. RESULTS: Molecular genetic analysis was performed in 11 patients and pathogenic mutations were identified in all cases: (mutation in myosin 7A gene in 5 cases; mutation in cadherin 23 gene in 6 cases). Four new mutations 2 in the MYO7A gene and 2 in the CDH23 gene never reported before were found. Walking delay and hearing level were not statistically correlated with the genotype abnormalities found. The speech discrimination skills, the speech production intelligibility and the academic performance were better in the group 1 children than the group 2 children after cochlear implantation. All the children of group 1 but one were in mainstreaming education. Specific language impairment was identified in two children of group 1. The group 3 children could not achieve open-set perceptive tasks after implantation--only closed-set word test can be done and their speech production remained unintelligible after cochlear implantation. CONCLUSION: Molecular analysis of Usher type I syndrome can ascertain the diagnosis in spite of the genetic heterogeneity. In this study, clinical symptoms weren't correlated with genotypic mutations. Speech discrimination skills, speech production quality, and academic performance were correlated with the age at implant.

Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%.

BACKGROUND: Usher syndrome, a devastating recessive disorder which combines hearing loss with retinitis pigmentosa, is clinically and genetically heterogeneous. Usher syndrome type 1 (USH1) is the most severe form, characterised by profound congenital hearing loss and vestibular dysfunction. OBJECTIVE: To describe an efficient protocol which has identified the mutated gene in more than 90% of a cohort of patients currently living in France. RESULTS: The five genes currently known to cause USH1 (MYO7A, USH1C, CDH23, PCDH15, and USH1G) were tested for. Disease causing mutations were identified in 31 of the 34 families referred: 17 in MYO7A, 6 in CDH23, 6 in PCDH15, and 2 in USH1C. As mutations in genes other than myosin VIIA form nearly 50% of the total, this shows that a comprehensive approach to sequencing is required. Twenty nine of the 46 identified mutations were novel. In view of the complexity of the genes involved, and to minimise sequencing, a protocol for efficient testing of samples was developed. This includes a preliminary linkage and haplotype analysis to indicate which genes to target. It proved very useful and demonstrated consanguinity in several unsuspected cases. In contrast to CDH23 and PCDH15, where most of the changes are truncating mutations, myosin VIIA has both nonsense and missense mutations. Methods for deciding whether a missense mutation is pathogenic are discussed. CONCLUSIONS: Diagnostic testing for USH1 is feasible with a high rate of detection and can be made more efficient by selecting a candidate gene by preliminary linkage and haplotype analysis.

Identification of a gene from Xp21 with similarity to the tctex-1 gene of the murine t complex.

Long range physical mapping within the p21 region of the X chromosome identified a CpG rich island approximately 180 kb centromeric to the chronic granulomatous disease (CGD) locus. The segments adjacent to the CpG island hybridized to discrete bands in DNAs of several species and when used to screen retinal cDNA libraries led to the identification of cDNAs that detected a mRNA of 2.1 kb in many tissues. Molecular characterization of corresponding genomic clones of this novel human gene confirmed the origin of the cDNA clones and indicated a genomic structure with five exons spanning a total of 9 kb. The complete cDNA sequence revealed that this gene contained a putative open reading frame of 116 amino acids with a 3' untranslated region of 1.74 kb. The amino acid sequence shows a high degree of similarity to the predicted product of the tctex-1 gene of the mouse t complex. As linkage studies and patients with deletions have implicated the Xp21 region as containing the retinitis pigmentosa defect (RP3), the gene was assessed as a candidate disease gene in RP3 families. A single base pair polymorphism was identified within the coding region but no disease associated changes were found by single strand conformational polymorphism and sequencing analysis of amplified exons of 20 RP patients. Analysis of a dinucleotide repeat polymorphism within this gene in families affected with RP3 suggested refinement of the RP3 region.