No evidence of linkage between the transforming growth factor-alpha gene in families with apparently autosomal dominant inheritance of cleft lip and palate.
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Eight families have been identified with cleft lip, with or without cleft palate (CL/P), inherited in an apparently autosomal dominant manner. Transforming growth factor-alpha (TGFA) has been tested as a candidate gene for clefting in these families. Negative lod scores were generated in an autosomal dominant model with 80% penetrance (Z = -3.152 at theta = 0.05 and Z = -2.49 at theta = 0.05 with only affected subjects scored). After testing with a reduced penetrance of 28%, less negative lod scores were generated (Z = -0.157 at theta = 0.00), but there was still no evidence of linkage. An autosomal recessive model with a penetrance of 35% was also tested. Regardless of the model used there was little evidence of linkage between TGFA and the CL/P phenotype, which is in contrast to the previously published findings of an association between TGFA and CL/P in unrelated subjects. (+info)
Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci.
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The first association study of cleft lip with or without cleft palate (CL/P), with candidate genes, found an association with the transforming growth-factor alpha (TGFA) locus. This finding has since been replicated, in whole or in part, in three independent studies. Here we extend our original analysis of the TGFA TaqI RFLP to two other TGFA RFLPs and seven other RFLPs at five candidate genes in 117 nonsyndromic cases of CL/P and 113 controls. The other candidate genes were the retinoic acid receptor (RARA), the bcl-2 oncogene, and the homeobox genes 2F, 2G, and EN2. Significant associations with the TGFA TaqI and BamHI RFLPs were confirmed, although associations of clefting with previously reported haplotypes did not reach significance. Of particular interest, in view of the known teratogenic role of retinoic acid, was a significant association with the RARA PstI RFLP (P = .016; not corrected for multiple testing). The effect on risk of the A2 allele appears to be additive, and although the A2A2 homozygote only has an odds ratio of about 2 and recurrence risk to first-degree relatives (lambda 1) of 1.06, because it is so common it may account for as much as a third of the attributable risk of clefting. There is no evidence of interaction between the TGFA and RARA polymorphisms on risk, and jointly they appear to account for almost half the attributable risk of clefting. (+info)
Programmed database system at the Chang Gung Craniofacial Center: part I.
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BACKGROUND: A database is a system for the management of information. Databases of different forms are widely used in everyday life from telephone books to online library catalogs. The Craniofacial Center at Chang Gung Memorial Hospital has seen over 20,000 patients during the past 20 years. All of the patient records need to digitally input into a computer database. METHODS: A database was custom designed using Paradox 8. The ACDSee Photo browser and DOS linked them to the original program. The Paradox 8 was programmed to a standard mode for the diagnosis and treatment data input to prevent typographical errors. RESULTS: We collected the records of 25,200 patients from 1987 to 2002, of which 24,331 underwent operations. The data for 14,828 patients were registered as complete and/or incomplete cleft and the proportions of unilateral to bilateral and female to male are presented in Table 1. CONCLUSION: This new database system was designed to ensure the accuracy of data input using a standard model that is capable of correct data programming using the custom designed coding system for the Craniofacial Center. The system also provides easy and reliable data retrieval when using the powerful search tools. (+info)
Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects.
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How folate reduces the risks of congenital anomalies is unknown. The authors focused on a gene involved in folate transport-reduced folate carrier-1 gene (RFC1). Using data from a California case-control study (1987-1989 births), the authors investigated whether the risks of orofacial clefts or conotruncal heart defects were influenced by a polymorphism of infant RFC1 or by an interaction between the RFC1 gene and maternal periconceptional use of vitamins containing folic acid. A total of 305 liveborn infants with cleft lip with or without cleft palate, 123 with cleft palate, 163 with conotruncal heart defects, and 364 nonmalformed controls were genotyped. Odds ratios of 1.6 (95% confidence interval: 0.9, 2.8) for the G80/G80 genotype and of 2.3 (95% confidence interval: 1.3, 3.9) for the G80/A80 genotype were observed relative to the A80/A80 genotype for conotruncal defects. Among mothers who did not use vitamins, the risk of conotruncal defects was 2.1 (95% confidence interval: 0.7, 5.9) for infants with genotype G80/G80 compared with those with the A80/A80 genotype. Among mothers who did use vitamins, the risk was 1.3 (95% confidence interval: 0.7, 2.7). Substantially elevated risks for either cleft group were not observed irrespective of genotype and use/nonuse of vitamins. Thus, this study found modest evidence for a gene-nutrient interaction between infant RFC1 genotype and periconceptional intake of vitamins on the risk of conotruncal defects. (+info)
Complex segregation analysis of 1,792 cleft lip and palate families in South America: 1967-1997.
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Although several studies have demonstrated familial aggregation of nonsyndromic cleft lip with or without cleft palate (CL/P), its model of inheritance remains uncertain. We report the results of complex segregation analysis performed in South American families with a newborn affected with CL/P. Families of 1,792 consecutive newborns affected with CL/P and registered during the period 1967 to 1997 were studied. A model that did not include a major locus was the best-fitting model for CL/P families. This result is in agreement with previous studies which showed a significant association of several putative susceptibility loci and CL/P, indicating that the genes involved in CL/P are likely to have only a very modest impact on disease risk. (+info)
Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2.
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Results from a genome-wide screen of 10 multiplex families ascertained through probands with nonsyndromic cleft lip with or without cleft palate (CL/P) in Mexico, Argentina, and the United States yielded suggestive evidence of linkage to chromosomes 2, 6, 17 and 18. Fine mapping excluded all regions except chromosome 2. Subsequent analysis was performed on the original 10 families plus an additional 16 families using 31 markers on chromosome 2. This analysis showed intriguing evidence of linkage to 2q (Zlr=2.26, empirical P-value=0.028 in a chromosome-wide analysis). Transmission disequilibrium tests also revealed evidence of linkage and disequilibrium for two markers in this region (D2S168 and D2S1400 with P-values=0.022 and 0.006, respectively). A subset of these 26 families provided additional evidence for a susceptibility gene for CL/P on 2q, suggesting that further studies of genes in this region are warranted. (+info)
Recent advances in primary palate and midface morphogenesis research.
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During the sixth week of human development, the primary palate develops as facial prominences enlarge around the nasal pits to form the premaxillary region. Growth of craniofacial components changes facial morphology and affects the extent of contact between the facial prominences. Our recent studies have focused on developing methods to analyze growth of the primary palate and the craniofacial complex to define morphological phases of normal development and to determine alterations leading to cleft lip malformation. Analysis of human embryos in the Carnegie Embryology Collection and mouse embryos of cleft lip and noncleft strains showed that human and mouse embryos have similar phases of primary palate development: first, an epithelial seam, the nasal fin, forms; then a mesenchymal bridge develops through the nasal fin and enlarges rapidly. A robust mesenchymal bridge must form between the facial prominences before advancing midfacial growth patterns tend to separate the facial components as the medial nasal region narrows and elongates, the nasal pits narrow, and the primary choanae (posterior nares) open posterior to the primary palate. In mouse strains with cleft lip gene, maxillary growth, nasal fin formation, and mesenchymal replacement of the nasal fin were all delayed compared with noncleft strains of mice. Successful primary palate formation involves a sequence of local cellular events that are closely timed with spatial changes associated with craniofacial growth that must occur within a critical developmental period. (+info)
Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts.
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Clefts of the lip and/or palate (CL/P) are among the most common birth defects worldwide. The majority are non-syndromic where CL/P occurs in isolation of other phenotypes. Where one or more additional features are involved, clefts are referred to as syndromic. Collectively CL/P has a major clinical impact requiring surgical, dental, orthodontic, speech, hearing and psychological treatments or therapies throughout childhood. The etiology of CL/P is complex and thought to involve both major and minor genetic influences with variable interactions from environmental factors. Using a combination of gene targeting technology and traditional developmental techniques in both mouse and chick, significant progress has been made in the identification of numerous genes and gene pathways critical for craniofacial development. Despite this, it has been a particular source of frustration that mutation screening of specific candidates, association studies and even genome-wide scans have largely failed to reveal the molecular basis of human clefting. Nevertheless, some important findings have recently come from studies involving syndromic forms of the disorder. These include several genes which have now been shown to contribute a major effect on the etiology of CL/P. Furthermore, these genes can also be used to demonstrate a significant overlap between syndromic and non-syndromic CL/P. The study of these syndromic genes and their molecular pathways will provide a useful and informative route with which to gain a better understanding of human craniofacial pathology. (+info)