Are oral clefts a consequence of maternal hormone imbalance? evidence from the sex ratios of sibs of probands

BACKGROUND: The causes of oral clefts (cleft lip with or without cleft palate, CL/P, and cleft palate alone, CP) have not been established. However, maternal intrauterine hormone profiles have been suspected of being involved. There is now substantial evidence that maternal hormone concentrations around the time of conception partially control the sexes of offspring. It is possible that the hormone profiles that control sex of offspring share features of the profiles suspected of causing clefts. This can be tested by examining the sex ratios (proportions male) of the unaffected sibs of probands. If these sex ratios are skewed in the same direction as that of probands, that suggests, ex hypothesi, maternal hormonal involvement in the causation of clefts. METHODS: Accordingly, a search was made for data on the sex ratios of the unaffected sibs of probands with clefts. For reasons given in the text, this search was informal rather than based on electronic data retrieval systems. Nine papers were located giving sex ratios of sibs of probands with CL/P and CP. RESULTS: Published data suggest that the sibs of probands with CL/P have a significantly higher sex ratio than the sibs of probands with CP. Thus the sib sex ratios are skewed in the same direction as those of the probands themselves. In other words, parents (mothers) of CL/P patients apparently have a tendency to produce boys, and parents of CP patients to produce girls. CONCLUSION: Accordingly, it is suggested that maternal hormone profiles may partially explain the unusual sex ratios (of probands and their sibs), as well as the malformations.     

CORRELATED MATINGS IN THE PARTIAL SELFER MIMULUS GUTTATUS

In partially selfing populations, siblings may be correlated for both selling and paternity. A model of the mating system based upon sampling pairs of progeny from a maternal parent is described. The model separates the correlation of selfing from the correlation of outcrossed paternal alleles and is an approach to paternity analysis suited for larger populations with fewer marker loci. Its parameters determine the components of genetic covariance between sibs and provide information about the average number of fathers in a maternal sibship. Electrophoretic markers were used to obtain estimates of correlated matings for two Mimulus guttatus populations. In both populations, about 50% selfing was observed. For two sibs randomly selected from the same capsule, the correlations of selfing between these sibs were 17% and 12% in the two populations, and the correlations of paternity (the proportion of full-sibs among outcrossed sib-pairs) were 37% and 44%. Sibs from different capsules were not correlated for selfing, and the paternity correlation dropped to near 20% in both populations. However, estimates of correlated matings have high variance, lack statistical independence, and can be difficult to obtain. The use of marker loci with many alleles can alleviate these problems.     

Periconceptional health and lifestyle factors of both parents affect the risk of live-born children with orofacial clefts

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO) are orofacial clefts and have a multifactorial etiology. The identification of amendable parental risk factors may contribute to a reduced occurrence of these malformations in the future. METHODS: Standardized demographic and periconceptional exposure data from 284 parents of a child with CL/P, 66 parents of a child with a CPO and 222 parents of a child without congenital malformations were collected at approximately 24 months after the periconceptional period of the index child. Univariate and multivariate logistic regression analyses were used to estimate relative risks by odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Univariate results suggest that low parental education, periconceptional maternal medication use and illnesses, paternal smoking, and first-trimester maternal common cold increased CL/P risk. Pregnancy planning and periconceptional folic acid supplementation, however, reduced CL/P risk by approximately 50% (OR, 0.5; 95% CI, 0.3-0.8) and 40% (OR, 0.6; 95% CI, 0.4-0.9), respectively. Mostly comparable results were obtained for CPO. Being a boy (OR, 2.0; 95% CI, 1.4-3.0), folic acid supplementation (OR, 0.6; 95% CI, 0.4-0.9), and low paternal education (OR, 1.6; 95% CI, 1.0-2.3) mainly determined CL/P in the multivariate analyses, compared to low paternal (OR, 4.5; 95% CI, 2.1-9.4) and maternal medication use (OR, 2.0; 95% CI, 1.0-4.0) for CPO. CONCLUSIONS: Preconceptional counseling for orofacial cleft risk assessment should pay attention to maternal medication use, periconceptional folic acid supplementation, and exposures of the father. These determinants can be amended, thereby modifying orofacial cleft risk.     

Birth order and oral clefts: a meta analysis

BACKGROUND: There is evidence that late birth order is associated with some complex disorders. For orofacial clefts there is no consensus as to whether increased birth order is associated or not. A meta-analysis of published data on cleft lip or cleft palate (CL/P and CP) was carried out to ascertain whether there is an increased risk for children of high birth order to have an oral cleft. METHODS: All data available with information regarding the frequency of live births and CL/P and CP cases by birth order (1, 2, 3, and 4 or more) were included in the analysis, and the birth order category "1" was considered to be with no risk (OR = 1.0). RESULTS: Children with higher birth order are more likely to have CL/P and CP with odds ratios increasing with birth order to a peak of 3.0 in children birth order "4 or more." Results are not different when isolated and syndromic cases are combined. CONCLUSIONS: CL/P and CP occurrence is correlated with increasing birth order. Further studies, taking into consideration sample size and factors such as income status, race, paternal age, vitamin intake, and social habits, should be done to determine conclusively the association between birth order and oral clefts.     

Epidemiological and genetic study of 200 cases of oral cleft in the Emilia Romagna region of northern Italy

Epidemiological and genetic variables in clefts were analyzed during the years 1978-1986 in a case-control study of congenital malformations in the Emilia Romagna region of northern Italy. Among 150,168 newborns, 200 cases of cleft were detected, yielding a prevalence of 1.33 per 1,000. These clefts consisted of 112 (0.075%) cases of cleft lip with or without cleft palate (CL +/- P) and 88 cases (0.058%) of cleft palate (CP). Coexisting abnormalities were found in 32% of cases. The heritability coefficient of CL +/- P was 0.84. No cluster in time or space could be demonstrated. Epilepsy was the only maternal risk factor found to be correlated with clefts. A predominance of males was found among CL +/- P cases.     

Congenital cleft lip and fluctuating dermatoglyphic asymmetry.

Fluctuating asymmetry for the palmar atd angle was studied in propositi born with CL(P) and their normal parents and sibs. The propositi with a family history of this congenital malformation were significantly different from the controls for this type of asymmetry. The propositi without a family history and the normal parents and sibs of both types of propositi were similar to the controls. The difference between the two types of propositi suggests that in some individuals a genetic mechanism may account for CL(P) and increased fluctuating asymmetry for this dermatoglyphic trait.     

Plasma zinc concentrations of mothers and the risk of nonsyndromic oral clefts in their children: a case-control study in the Philippines

BACKGROUND: Findings from animal experiments suggest a link between poor maternal zinc status and increased risk of oral clefts in offspring; however, there are few human studies on this issue. METHODS: A case-control study was conducted using 74 case mothers of children with nonsyndromic cleft lip with or without cleft palate (CL/P, n=57) or cleft palate alone (CP, n=17), and 283 control mothers of unaffected children recruited in the Philippines in early 2003. Maternal zinc status was assessed by determining plasma zinc concentrations a mean of 5 years after delivery of the index child. Odds ratios (ORs) of estimates of the relative risk of oral clefts were calculated for quartiles of maternal plasma zinc concentrations. RESULTS: The mean plasma zinc concentration of CL/P case mothers (9.6+/-1.2, SD micromol/l) was significantly lower than that in control mothers (10.1+/-1.6 micromol/l; P<0.05). Low plasma zinc concentrations (<11.0 micromol/l) were found in 88% and 94% of CL/P and CP case mothers, respectively, and in 72% of controls (P<0.05). The ORs for CL/P and CP combined, adjusted for potential confounding factors, decreased with increasing quartile of plasma zinc as follows: 1.0 (lowest quartile reference), 0.83 (95% confidence interval 0.37-1.89), 0.70 (0.31-1.68), and 0.26 (0.10-0.70) (P trend=0.008). CONCLUSIONS: Low plasma zinc concentrations were common in Filipino women of reproductive age, and higher plasma zinc concentrations were associated with a lower risk for oral clefts in their children.     

Association between MTHFR polymorphisms and orofacial clefts risk: a meta-analysis

BACKGROUND The roles of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in orofacial clefts (OFCs) risk have been substantially explored, but the results remain conflicting. To address this gap, we conducted a meta-analysis involving all eligible studies. METHODS: Electronic literature searches of the PubMed, EmBase, and Medline databases were performed up to October 31, 2011. Fixed-effects or random-effects models were used to calculate the pooled odds ratios (ORs) for two genetic comparisons (heterozygous mutation vs. wild type, homozygous mutation vs. wild type). RESULTS A total of 18 studies were ultimately identified. The pooled results revealed no statistical association between infant and maternal C677T and A1298C variants and risk of cleft lip with or without palate (CL/P) or cleft palate only (CPO), except for the maternal 677TT genotype for CL/P, the OR was 1.32 (95% confidence interval [CI], 1.06-1.63) as compared to the normal 677CC genotype. In the subgroup analyses on CL/P data based on ethnicity and source of control subjects, almost all of the results were replicated as nonsignificant associations in both examined polymorphisms, whereas the pooled risk estimate calculated for maternal 677TT genotype in the white population remained statistically significant, with an OR of 1.36 (95% CI, 1.05-1.76). CONCLUSIONS This meta-analysis suggests that maternal MTHFR 677TT genotype might increase the risk of having a CL/P offspring in the white population. However, these findings remain to be confirmed by additional investigations.     

HLA haplotype segregation in families of type 1 diabetics

The hypothesis of linkage between HLA and a disease susceptibility (DS) locus (or loci) for type 1 diabetes was tested. HLA segregation was random among 57 non-diabetic sibs but not among 39 diabetic sibs, suggesting that susceptibility to type 1 diabetes may be due to an HLA-linked gene(s). The data did not fit a genetic model involving either a single recessive or dominant gene. The excess of HLA-identical diabetic sibs and the reduced number who were HLA-discordant compared to expected numbers indicated that factors from both paternal and maternal haplotypes were necessary for DS. In 1 of the 3 families with a diabetic parent and more than one diabetic sib, the diabetic sibs inherited different haplotypes from the affected parent, suggesting that either of these haplotypes conferred DS. HLAB 8, B 18 and B 40 were increased in frequency among 97 unrelated type 1 diabetics compared with 238 controls, especially among those with onset age less than 10 years. This early onset group may represent a subtype of type 1 diabetes.     

Distribution of Affiliative Behavior Across Kin Classes and Their Fitness Consequences in Mandrills

Multimale–multifemale primate groups are ideal models to study the impact of kinship on the evolution of sociality. Indeed, the frequent combination of female philopatry and male reproductive skew produces social systems where both maternal and paternal kin are co‐resident. Several primates are known to bias their behavior toward both maternal and paternal kin. Moreover, allocation of affiliation toward paternal kin has been shown to depend on the availability in maternal kin: Female baboons invest more in paternal kin after the loss of preferred maternal kin. Here, we examined how affiliation co‐varies across kin classes in juvenile mandrills (Mandrillus sphinx), an Old World primate living in a multimale–multifemale society. While affiliation levels observed with the mother and with maternal half‐sibs co‐varied positively, especially in young females, we found that levels of affiliation among paternal half‐sibs correlated negatively with levels of affiliation among individuals from the same matriline (distant kin), possibly as a result of kin availability. In addition, in social species, social bonds between individuals have been linked to differentiated fitness consequences: More socially integrated individuals generally enjoy higher fitness. We therefore also tested whether affiliation during early life impacts fitness. We showed that the global amount of affiliation during juvenescence translated into possible reproductive benefits: Females who were more socially integrated gave birth on average a year before females that were less socially integrated. However, age at first reproduction was not predicted by the amount of affiliation exchanged with any particular kin class. These results add to the growing body of evidence demonstrating differential investment in bonding and possible social adjustments among different kin categories and emphasizing once more the adaptive value of sociality.     

Association between MTHFR polymorphisms and orofacial clefts risk: A meta‐analysis

BACKGROUND The roles of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in orofacial clefts (OFCs) risk have been substantially explored, but the results remain conflicting. To address this gap, we conducted a meta‐analysis involving all eligible studies. METHODS: Electronic literature searches of the PubMed, EmBase, and Medline databases were performed up to October 31, 2011. Fixed‐effects or random‐effects models were used to calculate the pooled odds ratios (ORs) for two genetic comparisons (heterozygous mutation vs. wild type, homozygous mutation vs. wild type). RESULTS A total of 18 studies were ultimately identified. The pooled results revealed no statistical association between infant and maternal C677T and A1298C variants and risk of cleft lip with or without palate (CL/P) or cleft palate only (CPO), except for the maternal 677TT genotype for CL/P, the OR was 1.32 (95% confidence interval [CI], 1.06–1.63) as compared to the normal 677CC genotype. In the subgroup analyses on CL/P data based on ethnicity and source of control subjects, almost all of the results were replicated as nonsignificant associations in both examined polymorphisms, whereas the pooled risk estimate calculated for maternal 677TT genotype in the white population remained statistically significant, with an OR of 1.36 (95% CI, 1.05–1.76). CONCLUSIONS This meta‐analysis suggests that maternal MTHFR 677TT genotype might increase the risk of having a CL/P offspring in the white population. However, these findings remain to be confirmed by additional investigations. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.     

Genetic Studies of Autistic Disorder and Chromosome 7

Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.     

Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios

Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts– the most common craniofacial birth defects in humans– are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions exists; only FOXE1 has been recognized as significantly associated with both CL/P and CP in genome-wide association studies (GWAS). We used a new statistical approach, PLACO (pleiotropic analysis under composite null), on a combined multi-ethnic GWAS of 2,771 CL/P and 611 CP case-parent trios. At the genome-wide significance threshold of 5 × 10⁻⁸, PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10⁻⁶, we found 5 more loci with compelling candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7), 3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). Additionally, we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2 loci in 19p13.12 (RAB8A) and 20q12 (MAFB) that appear to influence risk of both CL/P and CP in the same direction. We found locus-specific effects may vary by racial/ethnic group at these regions of genetic overlap, and failed to find evidence of sex-specific differences. We confirmed shared etiology of the two OFC subtypes comprising CL/P, and additionally found suggestive evidence of differences in their pathogenesis at 2 loci of genetic overlap. Our novel findings include 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. Our in-silico validation showed PLACO is robust to subtype-specific effects, and can achieve massive power gains over existing approaches for identifying genetic overlap between disease subtypes. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.     

Strategies for implementing genomic selection in family-based aquaculture breeding schemes: double haploid sib test populations

Background

Simulation studies have shown that accuracy and genetic gain are increased in genomic selection schemes compared to traditional aquaculture sib-based schemes. In genomic selection, accuracy of selection can be maximized by increasing the precision of the estimation of SNP effects and by maximizing the relationships between test sibs and candidate sibs. Another means of increasing the accuracy of the estimation of SNP effects is to create individuals in the test population with extreme genotypes. The latter approach was studied here with creation of double haploids and use of non-random mating designs.

Methods

Six alternative breeding schemes were simulated in which the design of the test population was varied: test sibs inherited maternal (Mat), paternal (Pat) or a mixture of maternal and paternal (MatPat) double haploid genomes or test sibs were obtained by maximum coancestry mating (MaxC), minimum coancestry mating (MinC), or random (RAND) mating. Three thousand test sibs and 3000 candidate sibs were genotyped. The test sibs were recorded for a trait that could not be measured on the candidates and were used to estimate SNP effects. Selection was done by truncation on genome-wide estimated breeding values and 100 individuals were selected as parents each generation, equally divided between both sexes.

Results

Results showed a 7 to 19% increase in selection accuracy and a 6 to 22% increase in genetic gain in the MatPat scheme compared to the RAND scheme. These increases were greater with lower heritabilities. Among all other scenarios, i.e. Mat, Pat, MaxC, and MinC, no substantial differences in selection accuracy and genetic gain were observed.

Conclusions

In conclusion, a test population designed with a mixture of paternal and maternal double haploids, i.e. the MatPat scheme, increases substantially the accuracy of selection and genetic gain. This will be particularly interesting for traits that cannot be recorded on the selection candidates and require the use of sib tests, such as disease resistance and meat quality.     

Parental origin and germline mosaicism of deletions and duplications of the dystrophin gene: a European study

Summary Knowledge about the parental origin of new mutations and the occurrence of germline mosaicism is important for estimating recurrence risks in Duchenne (DMD) and Becker muscular dystrophy (BMD). However, there are problems in resolving these issues partly because not all mutations can as yet be directly detected, and additionally because genetic ratios are very sensitive to ascertainment bias. In the present study, therefore, analysis was restricted to currently detectable mutations (deletions and duplications) in particular types of families which tend to be rare. In order to obtain sufficient data we pooled results from 25 European centers. In mothers of affected patients who were the first in their family with a dystrophin gene deletion or duplication, the ratio between the paternal and the maternal origin of this new mutation was 32:49 (binomial test P = 0.075) for DMD. In five BMD families the ratio between paternal and maternal origin of new mutations was 32. Recurrence risk because of maternal germline mosaicism was studied in sisters or subsequent sibs of isolated cases with an apparently new detectable mutation. In 12 out of 59 (0.20; 95% CI 0.10–0.31) transmissions of the risk haplotype the DMD mutation was transmitted as well. No recurrences were found in nine BMD families.     

Maternal diseases and isolated orofacial clefts in Hungary

BACKGROUND: Isolated orofacial clefts (OFCs) are likely to be caused by gene-environment interaction; therefore, the objective of the current study was to evaluate the possible association between all maternal diseases during pregnancy and isolated cleft lip with or without cleft palate (CL+/-CP) and posterior cleft palate (PCP) in the offspring. METHODS: The database of the large population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996, was evaluated. The database includes 1374 cases with isolated CL+/- CP and 601 with PCP, plus 38,151 matched population controls (without defects) and 20,868 patient controls with other defects. Data collection was based on prospective medical records, retrospective maternal data via a self-reported questionnaire, and home visits of nonresponding families. RESULTS: An increased risk for isolated CL+/- CP was found for children born to mothers with influenza, common cold, orofacial herpes, and gastroenteritis during pregnancy. Risk for isolated PCP was increased in children of mothers with influenza, sinusitis, and bronchitis. Among chronic maternal diseases, epilepsy and angina pectoris showed a higher prevalence in the mothers of children born with isolated OFCs (cases). CONCLUSIONS: Some maternal diseases are risk factors for the pathogenesis of isolated OFCs. It is worth considering the prevention of possible harmful effects of influenza by vaccination during the expected epidemic period.     

Age paternel: apport des données épidémiologiques et d'AMP

Introduction

Maternal age over 35 years is a well known risk factor in reproduction. This effect of maternal age had been demonstrated on the risk of infertility and the risk of miscarriage on the basis of epidemiological data and ART data, especially AID sources. In contrast, the effect of paternal age has been rarely analysed. The objective of this study was to review the literature analysing the effect of paternal age on the risk of infertility and the risk of miscarriage.

Material and method

Sixteen publications analysing paternal age were selected by a MEDLINE search. Thirteen publications concerned epidemiological data, based on surveys in the general population, surveys in pregnant women, case-control studies, and birth and death certificates. Three publications concerned ART data, based on IVF with ovum donation. In IVF with ovum donation, there is no correlation between paternal age and age of the female gamete donor.

Results

Seven epidemiological studies analysed the effect of paternal age on the risk of infertility. After controlling for maternal age, five studies showed a paternal age effect, and one showed a very weak paternal age effect. The last study did not show any paternal age effect, but only considered men under the age of 33 years. Three studies analysed the effect of paternal age on pregnancy rates in IVF with ovum donation. Only one study showed a paternal age effect. The four studies analysing the effect of paternal age on the risk of miscarriage showed a paternal age effect and two of the three studies based on birth and death certificates showed a paternal age effect on late foetal death (>20 weeks of gestation).

Conclusion

There are concordant data in the literature showing an effect of paternal age on the risk of infertility and the risk of miscarriage. Paternal age over 40 years could therefore be a risk factor in reproduction in the same way as maternal age over 35 years. Moreover, the risk of infertility and the risk of miscarriage could be much higher when both partners are over the age of 35–40 years.     

An aetiological study of 290 XXY males,with special reference to the role of paternal age

Summary Data on 290 non-mosaic 47,XXY males have been analysed for possible associations with parental ages at birth, season of birth, sex ratio among sibs, and twinning. Comparison with matched population controls revealed a highly significant association with parental age, which was fully explained by dependence on maternal age and maternal age alone. The maternal age effect was determined with greater precision than in an earlier study of the same material, in which siblings were used as controls, and was estimated to result in an increased risk of between 5% and 10% per annum (p.a.). The estimated independent effect of paternal age, after fitting maternal age, was marginally (but not significantly) negative, and excluded an increased risk in excess of 3% p.a. Paternal age therefore appears to have little if any independent significance in the aetiology of 47,XXY. After correcting for seasonal variations in the population birth rate and smoothing, there was a peak of XXY births in March and a trough in November. Though not statistically significant, the pattern resembled that reported in previous studies, and was similar for both younger and older mothers. The twinning rate for both the XXYs and their sibs, and the sex ratio among the latter, were close to the corresponding population values.     

Issues in analysis of data on paternal age and 47,+21: implications for genetic counseling for Down syndrome

Summary Data and analyses on paternal age and 47,+21 are reviewed. It is concluded that there are few, if any, grounds to justify the inference of a paternal age effect independent of maternal age for those paternal age-maternal age combinations on which there are prenatal diagnostic data. It is suggested that genetic counseling as to increased (or decreased) risk of Down syndrome associated with various paternal ages is not justified at present.     

Evidence of gene–environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate

Although multiple genes have been identified as genetic risk factors for isolated, non-syndromic cleft lip with/without cleft palate (CL/P), a complex and heterogeneous birth defect, interferon regulatory factor 6 gene (IRF6) is one of the best documented genetic risk factors. In this study, we tested for association between markers in IRF6 and CL/P in 326 Chinese case–parent trios, considering gene–environment interaction for two common maternal exposures, and parent-of-origin effects. CL/P case–parent trios from three sites in mainland China and Taiwan were genotyped for 22 single nucleotide polymorphisms (SNPs) in IRF6. The transmission disequilibrium test was used to test for marginal effects of individual SNPs. We used PBAT to screen the SNPs and haplotypes for gene–environment (G × E) interaction and conditional logistic regression models to quantify effect sizes for SNP–environment interaction. After Bonferroni correction, 14 SNPs showed statistically significant association with CL/P. Evidence of G × E interaction was found for both maternal exposures, multivitamin supplementation and environmental tobacco smoke (ETS). Two SNPs showed evidence of interaction with multivitamin supplementation in conditional logistic regression models (rs2076153 nominal P = 0.019, rs17015218 nominal P = 0.012). In addition, rs1044516 yielded evidence for interaction with maternal ETS (nominal P = 0.041). Haplotype analysis using PBAT also suggested interaction between SNPs in IRF6 and both multivitamin supplementation and ETS. However, no evidence for maternal genotypic effects or significant parent-of-origin effects was seen in these data. These results suggest IRF6 gene may influence risk of CL/P through interaction with multivitamin supplementation and ETS in the Chinese population.