Учебники / Genetic Hearing Loss Willems 2004
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for example, the T!C change in exon 13 at base 1360, have been observed in more than one unrelated family (33). The data generated by our study and by others (30–37) add further support that no common EYA1 mutation is associated with BOR syndrome. Interestingly, however, most of the mutations are clustered in the C-terminal region and within the EYA1 homologous region or, exon 8 and exon 10 are commonly involved. While the e ect of these mutations is not known, because the two nonsense mutations result in premature stop codons in exons 8 and 10 and mutations have been reported in the N-terminal region, it is possible that the phenotype reflects a dosage e ect. The finding of splice site mutations (IVS 8-1 G!A) that alter correct EYA1 splicing, resulting in exon skipping and premature truncation, supports this hypothesis.
About 65% of persons examined in our study did not have detectable mutations in the coding region of EYA1. To determine the prevalence of EYA1 mutations in the syndrome, it is essential to screen for mutations in the UTRs, promoters, and intronic regions. It is unlikely that tightening diagnostic criteria for BOR syndrome will improve the correlation with EYA1 mutations. A variety of EYA1 mutations produce a continuum of disease, ranging from typical BOR to a mild clinical phenotype even within the same family. No obvious genotype-phenotype relationship could be discerned.
Further clinical studies of BOR syndrome should focus on detailed dysmorphology; genetic studies should be targeted to a more thorough mutation screen of EYA1. Families with undetected mutations should be verified for linkage to chromosome 8q and 1q to detect genetic heterogeneity. Our current results indicate the involvement of a third locus associated with branchial anomalies (73; Kumar et al., unpublished report). Also, two large families presenting with clinical features of branchio-otic type syndrome (62,64) have recently been reported that are unlinked to the BOR gene (8q region), indicating that mutations in other genes can produce phenotypes that overlap, at least some extent, with BOR syndrome. Thorough dysmorphological studies may reveal clinical features that permit unambiguous genotype-phenotype correlations, much as dystopin canthorm in Waardenburg syndrome, another heterogeneous developmental disorder with variable expressivity, implies mutations in PAX3 and not MITF.
V.GENETIC TESTING AND GENOTYPE-PHENOTYPE CORRELATION
Recent mapping of new loci and identification of the EYA1 gene have opened a door to the evaluation of possible correlations between specific mutations and the observed clinical variability. Unfortunately, to date, no
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distinct genotype-phenotype relationships have been demonstrated. This is due to the fact that a variety of EYA1 mutations can produce a high degree of clinical variability among the patients with typical and atypical manifestations. In typical BOR, all three organs—branchial, auditory, and renal— are involved. However, atypical or variant and isolated cases are characterized by involvement limited to one or two organ systems, such as BO or BR. In our studies, no significant correlation between EYA1 mutations of di erent types (33) and mild versus severe disease were found. However, correlations may be possible when a larger data series on genotype-pheno- type and severity of the disease is available. With regard to genetic testing, several genetic diseases (e.g., polycystic kidney disease, cystic fibrosis, Usher syndrome type 2A, connexin 26 deafness, etc.) have common mutations, some of which are specific to particular ethnic groups. However, in BOR, several mutations have been described but no associations between specific mutations and particular ethnic populations have been reported. This makes genetic testing or counseling very di cult. It would be extremely helpful to determine whether there are such relationships. This would have important implications for genetic counseling and population screening to detect mutation carriers. We are now in the process of collecting BOR families from all over the world and a detailed study is underway in our laboratory to establish whether ethnic/racial-based di erences exist in the mutations in the EYA1 gene.
In summary, the major clinical features of a typical BOR syndrome are hearing loss (conductive, sensorineural, or mixed), branchial arch anomalies (preauricular pits, structural defects of the outer, middle, or inner ear, fistulas, cysts, or sinuses), and renal defects (hypoplasia or no kidney, renal agenesis). In several families in which the BOR phenotype segregates, mutations have been identified in the EYA1 gene. However, in many a ected families, mutation screening of EYA1 has failed to document any allele variations. To determine the prevalence of mutations in the EYA1-coding region in persons with phenotypic features consistent with BOR syndrome, we screened 70 unrelated kindreds for EYA1 allele variants. Several novel mutations were identified, and with the previously described mutations, suggest that EYA1 allele variants in the coding region can be detected in 25–30% of persons with BOR syndrome. These findings imply either that the majority of BORcausing mutations lie in intronic and/or 5V-3V-untranslated regions, involve chromosome rearrangement of the gene, or that the disease is genetically heterogeneous. Also, the absence of any common mutations associated with the EYA1 gene somewhat reduces the likelihood of being able to o er testing using limited mutation panels in targeted populations, or the general population overall. However, mapping and cloning the other genes associated with branchiogenic disorders will have an important impact, leading
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to a more comprehensive understanding of the pathogenesis and etiology of this syndrome. How the BOR gene(s) influence both branchial/auditory and renal development is an interesting question. What is the common denominator in the development of both organs and what is the function of the gene associated with BOR? The delineation of gene(s) that exert control over branchial/auditory and/or renal development should shed considerable light on their underlying developmental processes and would define the spectrum of defects associated with this syndrome.
ACKNOWLEDGMENTS
I wish to thank all the family members for donating the blood samples and their participation in this research. I am also thankful to Dr. William J. Kimberling and Dr. Dana Orten for their valuable comments and suggestions. This work was supported by a grant from the National Institute of Dental and Craniofacial Research (NIDCR) 1 R01 DE14090-01.
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10
Treacher Collins Syndrome
Jill Dixon and Michael J. Dixon
University of Manchester, Manchester, England
I.INTRODUCTION
Although the condition was probably first described by Thompson in 1846 (1), Treacher Collins syndrome (TCS) is eponymously named after the ophthalmologist E. Treacher Collins, who described the essential components of the syndrome in 1900 (2). However, Franceschetti and Klein, who used the term mandibulofacial dysostosis to describe the facial appearance, detailed the first complete description of the condition (3).
II.CLINICAL FEATURES OF TREACHER COLLINS SYNDROME
TCS is an autosomal dominant disorder of facial development that a ects approximately 1 in 50,000 live births (4,5). However, more than 60% of cases do not appear to have a previous family history and are thought to arise as the result of a spontaneous mutation (6). The major clinical features of TCS, with their frequencies in parentheses (7), include abnormalities of the external ears (77%) and atresia of external auditory canals (36%). Radiographic analysis of the middle ears of a ected individuals has revealed malformation of the auditory ossicles with fusion between rudiments of the malleus and incus, partial absence of the stapes and oval window, or even complete absence of the middle ear and epitympanic space (8). As a result of these abnormalities, bilateral conductive hearing loss is common (50% of cases), whereas mixed or sensorineural hearing loss is rare (9). Lateral downward
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