Cystathionine beta-synthase c.844ins68 gene variant and non-syndromic cleft lip and palate

Rubini, Michele; Brusati, Roberto; Garattini, G.; Magnani, Cinzia; F, Liviero; Bianchi, Fabrizio; Tarantino, Enrico; Massei, Alessandro; Pollastri, Susanna; Carturan, S.; Amadori, Alice; Bertagnin, Elisa; Cavallaro, A.; Fabiano, Anna; A, Franchella; Calzolari, Elisa

doi:10.1002/ajmg.a.30812

Cited by 31 publications

(39 citation statements)

References 41 publications

(39 reference statements)

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“…3A). These results were modest and not concordant with a previous study of this gene in clefts [Rubini et al, 2005]. CBS performs the rate-limiting step in the transsulfuration pathway that degrades homocysteine [Finkelstein, 1990], and this SNP was associated with a decrease in the total homocysteine/cystathionine ratio [Fredriksen et al, 2007].…”

Section: Discussioncontrasting

confidence: 91%

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Folate and one‐carbon metabolism gene polymorphisms and their associations with oral facial clefts

Boyles

Wilcox

Taylor

et al. 2008

American J of Med Genetics Pt A

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Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts.

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Section: Discussioncontrasting

confidence: 91%

“…k Zhu et al [2005]. l Rubini et al [2005]. have suggested protection from CL/P by the MTHFR T allele in mothers [van Rooij et al, 2003;Gaspar et al, 2004;Nurk et al, 2004] and children [Shaw et al, 1998;Grunert et al, 2002;Shotelersuk et al, 2003;Gaspar et al, 2004], although none reached statistical significance.…”

Section: Discussionmentioning

confidence: 99%

Folate and one‐carbon metabolism gene polymorphisms and their associations with oral facial clefts

Boyles

Wilcox

Taylor

et al. 2008

American J of Med Genetics Pt A

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“…Furthermore, because parent-of-origin effects have been previously described for oral-cleft candidate genes (Scapoli et al 2002;Rubini et al 2005), we tested TGFB3 variants for evidence of genomic imprinting. Interestingly, however, we found evidence of a lower risk of maternal transmission compared with paternal transmission (I M = 0.38; CI: 0.17-0.86) of allele T to the affected offspring at marker rs2300607 (IVS1 +5321) (Table 3).…”

Section: Discussionmentioning

confidence: 99%

“…As this is the most convincing human study of TGFB3 in CL/P published to date, we investigated the relevance of their findings for CL/P patients of a different ethnic background, namely, patients of central European origin. In addition, we searched for parent-of-origin effects, which have been previously described for candidate genes associated with nonsyndromic oral clefts (Scapoli et al 2002;Rubini et al 2005). …”

Section: Introductionmentioning

confidence: 99%

TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate

et al. 2008

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Mice with a deletion of Tgf-b3 (-/-) and association studies in humans of different ethnicities support the involvement of TGFB3 in the etiology of orofacial clefts. In this study, we investigated the relevance of TGFB3 in the development of cleft lip and palate (CL/P) among 204 triads of central European origin. Transmission-disequilibrium test (TDT) analysis revealed no significant transmission distortions for each marker alone, and none for any possible haplotypes. However, we found strong evidence for parent-of-origin effects, with lower risk of maternal transmission compared with paternal transmission [I M = 0.38; confidence interval (CI): 0.17-0.86] of the risk allele T to an affected offspring at marker rs2300607. This is also expressed in an increased risk of heterozygous children having the T allele inherited from the father (R P = 3.47; CI: 1.32-9.11). Our data support the involvement of TGFB3 in the development of oral clefts in patients of central European origin.

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“…For example, functional RFC1 and MTHFR variants in probands revealed no association with CL/P in a South American population [62]. However, a log-linear-based method revealed a geneenvironment interaction between CP infants carrying either CT or TT genotypes at MTHFR and maternal folic acid consumption [63] and another study found similar findings for CL/P [64]. Also, an increased risk has been observed for maternal MTHFR variants [65,66].…”

Section: Genes In Environmental Pathwaysmentioning

confidence: 99%

Progress toward discerning the genetics of cleft lip

Lidral

Moreno

2005

Current Opinion in Pediatrics

111

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Purpose of review-Orofacial clefts are common birth defects with a known genetic component to their etiology. Most orofacial clefts are nonsyndromic, isolated defects, which can be separated into two different phenotypes: (1) cleft lip with or without cleft palate and (2) cleft palate only. Both are genetically complex traits, which has limited the ability to identify disease loci or genes. The purpose of this review is to summarize recent progress of human genetic studies in identifying causal genes for isolated or nonsyndromic cleft lip with or without cleft palate.Recent findings-The results of multiple genome scans and a subsequent meta-analysis have significantly advanced our knowledge by revealing novel loci. Furthermore, candidate gene approaches have identified important roles for IRF6 and MSX1. To date, causal mutations with a known functional effect have not yet been described.Summary-With the implementation of genome-wide association studies and inexpensive sequencing, future studies will identify disease genes and characterize both gene-environment and gene-gene interactions to provide knowledge for risk counseling and the development of preventive therapies.

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Cystathionine beta-synthase c.844ins68 gene variant and non-syndromic cleft lip and palate

Cited by 31 publications

References 41 publications

Folate and one‐carbon metabolism gene polymorphisms and their associations with oral facial clefts

Folate and one‐carbon metabolism gene polymorphisms and their associations with oral facial clefts

TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate

Progress toward discerning the genetics of cleft lip

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