of the mutant auditory phenotype of the keratitis-ichthyosis-deafness (KID) syndrome in a series of 5 patients. KID syndrome is a rare genodermatosis caused by missense mutations of the GJB2 (connexin 26) gene. The deafness is typically severe-to-profound, although one case was less severe. Progression of hearing loss is unusual. Rehabilitating the communication deficits in KID syndrome is especially difficult since the visual defect often prevents the use of sign language, and the severe skin disorder often prohibits the continuous use of hearing amplification devices. 2. We have collaborated with the Section on Human Genetics on the phenotypic characterization and positional cloning of the gene, TMIE, underying nonsyndromic recessive deafness DFNB6. TMIE is a novel gene that is also mutated in the spinner mouse mutant which has recessive deafness. The function of TMIE is unknown. Human subjects with homozygous TMIE mutations have severe-to-profound nonsyndromic hearing loss. 3. We have collaborated with the Section on Human Genetics on the phenotypic characterization and positional cloning of the gene, TFCP2L3, underying nonsyndromic dominant deafness DFNA28. TFCP2L3 is a novel gene with sequence similarity to a family of transcription factors. We ascertained a single large family segregating a frameshift mutation of TFCP2L3, with the resulting phenotype of postlingual, progressive sensorineural hearing loss. 4. We are collaborating with the Section on Human Genetics on the phenotypic characterization and identification of mutations underlying Usher syndrome in Ashkenazi Jews. 5. We have collaborated with the Section on Human Genetics on the identification of the gene, USH1C, underlying nonsyndromic recessive deafness DFNB18. USH1C mutations can also cause type 1C Usher syndrome. 6. We have collaborated with the Section on Human Genetics on the phenotypic characterization of DFNB21 deafness, which is caused by homozygosity for null alelles of the TECTA gene encoding alpha-tectorin. These individuals have nonprogressive, prelingual, moderate-to-severe sensorineural hearing loss primarily affecting middle frequencies. This phenotype is distinctive and may be used to guide genetic diagnosis of hereditary hearing loss. 7. We continue to study the phenotypic expression and genotypic basis of hearing loss associated with enlarged vestibular aqueducts (EVA) in humans. Approximately 1/3 of patient have 2 Pendred syndrome gene (PDS) mutations, 1/3 are heterozygous for PDS mutations, and 1/3 have no detectable PDS mutations. There appears to be a correlation of PDS genotype with both the auditory and thyroid (goiter) phenotypes: only patients with 2 PDS mutations have goiter and/or an abnormal perchlorate discharge test of the thyroid iodination defect in Pendred syndrome. Patients with 2 PDS mutations have more severe hearing loss that always appears to be bilateral, in contrast to generally less severe hearing loss that may be unilateral in the patients with one or zero PDS mutations. We are testing the hypothesis that there are other genetic causes of EVA by using a candidate gene mutation analysis approach in EVA patients with only 1 or 2 PDS mutations. 8. We are characterizing the auditory phenotype of patients with Turner syndrome. We have determined that there are 2 distinctive patterns of sensorineural hearing loss in this disorder. The presence of sensorineural hearing loss does not appear to be correlated with eustachian tube dysfunction and chronic otitis media, which are common in this population. Finally, we have identified an unusual morphology to the high-arched palate which is a well-known phenotypic feature of this disorder. This palatal phenotype may be used to help diagnose Turner syndrome in young, very mildly affected patients with Turner syndrome who present with chronic otitis media or sensorineural hearing loss.
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