Cleft Lip and the detrimental effect of low periconceptional folate

A recent warning from the Food and Drug Administration has notified healthcare professionals and patients of an increased risk of develop of clip lip and or cleft palate in infants born to women treatment with certain medications during pregnancy.  Fortunately, there is an entire body of work that explores these birth defects.
One interesting study is called, "Does the Interaction between Maternal Folate Intake and the Methylenetetrahydrofolate Reductase Polymorphisms Affect the Risk of Cleft Lip with or without Cleft Palate?" by Iris A. L. M. van Rooij, Christl Vermeij-Keers, Leo A. J. Kluijtmans, Marga C. Ocké, Gerhard A. Zielhuis, Sieneke M. Goorhuis-Brouwer, Jan-Jaap van der Biezen, Anne-Marie Kuijpers-Jagtman and Régine P. M. Steegers-Theunissen - Am. J. Epidemiol. (2003) 157 (7): 583-591.  Here is an excerpt: "Abstract -
Periconceptional folic acid supplementation may reduce the risk of cleft lip with or without cleft palate (CL(P)). Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability of 5-methyltetrahydrofolate, the predominant circulating form of folate. To determine the effect of MTHFR C677T and MTHFR A1298C genotypes and haplotypes on CL(P) risk and the interaction with maternal periconceptional dietary folate and folic acid supplement intake, the authors conducted a case-control triad study in the Netherlands (1998–2000) among 179 CL(P) and 204 control families. Infant and parental MTHFR C677T and MTHFR A1298C genotypes and haplotypes were not associated with CL(P) risk in the case-control and transmission disequilibrium test analyses. Mothers carrying the MTHFR 677TT genotype and who either did not use folic acid supplements periconceptionally or had a low dietary folate intake, or both, had an increased risk of delivering a CL(P) child (odds ratio (OR) = 5.9, 95% confidence interval (CI): 1.1, 30.9; OR = 2.8, 95% CI: 0.7, 10.5; OR = 10.0, 95% CI: 1.3, 79.1, respectively). No supplement use, low dietary folate intake, and maternal MTHFR 1298CC genotype increased the risk of CL(P) offspring almost sevenfold (OR = 6.5, 95% CI: 1.4, 30.2). Thus, the detrimental effect of low periconceptional folate intake on the risk of giving birth to a CL(P) child was more pronounced in mothers with the MTHFR 677TT or MTHFR 1298CC genotype."

Another interesting study is called, "Studies of the Candidate Genes TGFB2, MSX1, TGFA, and TGFB3 in the Etiology of Cleft Lip and Palate in the Philippines" - The Cleft Palate-Craniofacial Journal: January 1997, Vol. 34, No. 1, pp. 1-6.  by Andrew C. Lidral, D.D.S., Jeffrey C. Murray, M.D., Kenneth H. Buetow, Ph.D., Ann M. Basart, Heidi Schearer, Rita Shiang, Ph.D., Avelina Naval, Eriberto Layda, M.D., Kathy Magee, R.N., and William Magee, M.D., D.D.S.  Here is an excerpt: "Abstract - Population-based candidate-gene studies can be an effective strategy for identifying genes involved in the etiology of disorders where family-based linkage studies are compromised by lack of access to affected members, low penetrance, and/or genetic heterogeneity. We evaluated association data for four candidate genes using a population from the Philippines that is genetically separate from previously studied Caucasian populations. Case ascertainment was made possible by collaboration with Operation Smile, a volunteer medical organization, which facilitated identification of a large number of cases for study. A new allelic variant of transforming growth factor-beta3 was identified to use in these studies. After exclusion of syndromic cases of cleft lip and palate, no evidence for association with previously reported allelic variants of transforming growth factor-beta2 (TGFB2), homeobox 7 (MSX1), or transforming growth factor-alpha (TGFA), or with the new TGFB3 variant was detected. Previous association studies using Caucasian populations of nonsyndromic cleft lip and/or palate (CL/P) and cleft palate only (CPO) have strongly suggested a role for TGFA in the susceptibility of clefting in humans. Exclusion of significant association in a non-Caucasian population for TGFA suggests that TGFA plays less of a role than it does in Caucasians. This may be due to multiple or different genetic and/or environmental factors contributing to the etiology of this most common craniofacial anomaly in the Philippine population."
Another interesting study is called, "Familial recurrence-pattern analysis of cleft lip with or without cleft palate." By M Farrall and S Holder - Division of Molecular Medicine, Medical Research Council Clinical Research Centre, Harrow, England. Am J Hum Genet. 1992 February; 50(2): 270–277.  Here is an excerpt: "Abstract - Cleft lip with or without cleft palate (CL/P) is a common congenital malformation with an incidence in European white populations of about 1/1,000. The familial clustering of CL/P has been extensively characterized, and epidemiological studies have proposed monogenic models (with reduced penetrance), multifactorial/threshold models, and mixed major-gene/multifactorial models to explain its inheritance. The recognition of an association between two RFLPs at the transforming growth factor alpha (TGFA) locus and CL/P supports a major-gene component to the etiology of CL/P. Risch has shown that the recurrence risk ratio lambda R (risk to relatives, vs. population prevalence) is a useful pointer to the mode of inheritance. Here we further develop the use of lambda R to analyze recurrence-risk data for CL/P. Recurrence risks for first-, second-, and third-degree relatives equate well with oligogenic models with as few as four loci. A monogenic/additive model is strongly rejected. The limited available twin data are also consistent with this model. A "major gene" interacting epistatically with an oligogenic background is shown to be a plausible alternative. Power calculations for a linkage study to map the CL/P major-risk locus suggest that a sample of 50 affected sib pairs will be adequate, but linkage to minor-risk loci will require very much larger samples."

We all owe a debt of gratitude to these researchers for their fine work and dedication.  For more information, please read the studies in their entirety.