Transforming Growth Factor-α (TGFA): Genomic Structure, Boundary Sequences, and Mutation Analysis in Nonsyndromic Cleft Lip/Palate and Cleft Palate Only

Machida, Junichiro; Yoshiura, Koh-ichiro; Funkhauser, Carrie; Natsume, Nagato; Kawai, Takeshi; Murray, Jeffrey C.

doi:10.1006/geno.1999.5962

Cited by 40 publications

(28 citation statements)

References 33 publications

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“…No mutations were found in searches of the gene causing ectrodactyly, ectodermal dysplasia, and cleft lip and palate syndrome 3, protein 63 (P63; Barrow et al, 2002), and only rare variants of unclear etiologic significance were found in searches of transforming growth factor beta 3 (TGFB3; Lidral et al, 1998) and transforming growth factor alpha (TGFA; Machida et al, 1999). The MSX1 gene has been shown to harbor mutations in about 2% of cases of isolated clefting (Jezewski et al, 2003;Suzuki et al, 2004), as has the T-box 22 (TBX22) gene for a very small percentage of cases of isolated cleft palate (Marcano et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Contributions of PTCH Gene Variants to Isolated Cleft Lip and Palate

Mansilla¹,

Cooper²,

Goldstein³

et al. 2005

Cleft Palate-Craniofac J

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Objective-Mutations in patched (PTCH) cause the nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome. Nevoid basal cell carcinoma syndrome may present with developmental anomalies, including rib and craniofacial abnormalities, and predisposes to several tumor types, including basal cell carcinoma and medulloblastoma. Cleft palate is found in 4% of individuals with nevoid basal cell carcinoma syndrome. Because there might be specific sequence alterations in PTCH that limit expression to orofacial clefting, a genetic study of PTCH was undertaken in cases with cleft lip and/or palate (CL/P) known not to have nevoid basal cell carcinoma syndrome.Results-Seven new normal variants spread along the entire gene and three missense mutations were found among cases with cleft lip and/or palate. One of these variants (P295S) was not found in any of 1188 control samples. A second variant was found in a case and also in 1 of 1119 controls. The third missense (S827G) was found in 5 of 1369 cases and in 5 of 1104 controls and is likely a rare normal variant. Linkage and linkage desequilibrium also was assessed using normal variants in and adjacent to the PTCH gene in 220 families (1776 individuals), each with two or more individuals with isolated clefting. Although no statistically significant evidence of linkage (multipoint HLOD peak = 2.36) was uncovered, there was borderline evidence of significant transmission distortion for one haplotype of two single nucleotide polymorphisms located within the PTCH gene (p = .08).Conclusion-Missense mutations in PTCH may be rare causes of isolated cleft lip and/or palate.An as yet unidentified variant near PTCH may act as a modifier of cleft lip and/or palate.

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Section: Discussionmentioning

confidence: 99%

Contributions of PTCH Gene Variants to Isolated Cleft Lip and Palate

Mansilla¹,

Cooper²,

Goldstein³

et al. 2005

Cleft Palate-Craniofac J

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“…There is the possibility, however, that the marker is in linkage disequilibrium with a yet unidentified causally relevant mutation that is responsible for the observed increase in risk. To address this concern, Machida et al [1999] performed a mutation analysis of the entire coding sequence of TGFA, and eight new variants were identified. Even so, no significant differences were found when the variants were used in single comparisons to test for association among 89 nonsyndromic CPO cases and 278 controls.…”

Section: Cleft Palate Only (Cpo)mentioning

confidence: 99%

Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: A case‐parent triad analysis

Jugessur

Lie

Wilcox

et al. 2003

Genetic Epidemiology

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We selected 262 case-parent triads from a population-based study of orofacial clefts in Norway, and examined variants of developmental genes TGFA, TGFB3, and MSX1 in the etiology of orofacial clefts. One hundred seventy-four triads of cleft lip cases (CL+/-P) and 88 triads of cleft palate only cases (CPO) were analyzed. There was little evidence for an association of any of these genes with CL+/-P. The strongest association was a 1.7-fold risk with two copies of the TGFB3-CA variant (95% CI=0.9-3.0). Among CPO cases, there was a 3-fold risk with two copies of the TGFA TaqI A2 allele, and no increase with one copy. Assuming this to be a recessive effect, we estimated a 3.2-fold risk among babies homozygous for the variant (95% CI=1.1-9.2). Furthermore, there was strong evidence of gene-gene interaction. While there was only a weak association of the MSX1-CA variant with CPO, the risk was 9.7-fold (95% CI=2.9-32) among children homozygous for both the MSX1-CA A4 allele and the TGFA A2 allele. No association of CPO with the TGFA variant was seen among the other MSX1-CA genotypes. In conclusion, no strong associations were found between CL+/-P and variants at these three genes. There was a possible recessive effect of the TGFA TaqI variant on the risk of CPO, with a 3-fold risk among children homozygous for the variant. The effect of this TGFA genotype was even stronger among children homozygous for the MSX1-CA A4 allele, raising the possibility of interaction between these two genes.

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“…These analyses considered individual characteristics (gender and race) as well as potential genetic modifiers of the palatal phenotype. Potential genetic modifiers were selected based on published reports providing evidence of linkage or association between a genetic variant and facial clefts in humans and included: transforming growth factor α (TGFA) (Ardinger et al, 1989;Machida et al, 1999;Mitchell, 1997), transforming growth factor β three (TGFB3) (Lidral et al, 1998), and muscle segment homeobox (MSX1) (Fallin et al, 2003;Jezewski et al, 2003;Lidral et al, 1998; reviewed in Marazita and Neiswanger, 2002). In addition, because there is evidence that the risk of facial clefts may be influenced by maternal folate intake (van Rooij et al, 2004), variants of genes involved in the folate-homocysteine metabolic pathway, including methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine beta synthase (CBS) (reviewed in Finnell et al, 1998), were evaluated.…”

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confidence: 99%

Evaluation of Potential Modifiers of the Palatal Phenotype in the 22q11.2 Deletion Syndrome

Driscoll

Boland

Emanuel

et al. 2006

Cleft Palate-Craniofac J

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Objective-To evaluate potential modifiers of the palatal phenotype in individuals with the 22q11.2 deletion syndrome.Design-Data from 356 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the palatal phenotype. Specifically, subjects with and without velopharyngeal inadequacy and/or structural malformations of the palate were compared with respect to gender, race, and genotype for variants of seven genes that may influence palatal development.Methods-The chi-square test or Fisher exact test was used to evaluate the association between palatal phenotype and each potential modifier. Odds ratios and their associated 95% confidence intervals were used to measure the magnitude of the association between palatal phenotype, subject gender and race, and each of the bi-allelic variants.Results-The palatal phenotype observed in individuals with the 22q11.2 deletion syndrome was significantly associated with both gender and race. In addition, there was tentative evidence that the palatal phenotype may be influenced by variation within the gene that encodes methionine synthase.Conclusions-Variation in the palatal phenotype observed between individuals with the 22q11.2 deletion syndrome may be related to personal characteristics such as gender and race as well as variation within genes that reside outside of the 22q11.2 region. Keywords chromosome 22q11.2 deletion; genes; genotype; palate; penetrance; phenotype Hemizygous deletion of the chromosome 22q11.2 region results in a syndromic phenotype that encompasses the DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Population-based estimates of the prevalence of this deletion range from 1 in 4500 to 1 in 7100 births (Botto et al., 2003;Tezenas du Montcel et al., 1996;Oskarsdottir et al., 2004), making it the most frequent known interstitial deletion in humans. The majority of individuals with the 22q11.2 deletion syndrome have a de novo three-megabase deletion. However, approximately 10% of patients with the 22q11.2 deletion syndrome have an inherited deletion, and approximately 10% have a smaller deletion (1.5 Mb) (Saitta et al., 2004;Yamagishi and Srivastava, 2003).The phenotypic consequences of hemizygous deletion of chromosome 22q11.2 are remarkably variable and can include cardiac, thymic, parathyroid, craniofacial, developmental, neurologic, and behavioral manifestations. None of these features appears to be fully penetrant, and each exhibits variable expressivity. For example, approximately 75% of patients with the 22q11.2 deletion syndrome have a cardiac defect, and a range of malformations (e.g., tetralogy of Fallot, interrupted aortic arch, septal defects) is observed among those who have such a defect (McDonald-McGinn et al., 1997;Ryan et al., 1997).The variability in the 22q11.2 deletion syndrome phenotype is largely unexplained. Variability is observed across unrelated patients and between affected family members who have presumably inherited identical deletions (Desmaze et al., 1993;McLe...

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Transforming Growth Factor-α (TGFA): Genomic Structure, Boundary Sequences, and Mutation Analysis in Nonsyndromic Cleft Lip/Palate and Cleft Palate Only

Cited by 40 publications

References 33 publications

Contributions of PTCH Gene Variants to Isolated Cleft Lip and Palate

Contributions of PTCH Gene Variants to Isolated Cleft Lip and Palate

Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: A case‐parent triad analysis

Evaluation of Potential Modifiers of the Palatal Phenotype in the 22q11.2 Deletion Syndrome

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