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PubMed2001

Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate.

The malformation of nonsyndromic cleft lip with or without cleft palate (CL/P) is a common congenital disease that affects approximately 1/1000 newborns in Caucasian populations. Genetic studies indicate that CL/P has the characteristics of a complex genetic trait. Linkage analysis and mouse-model knockout studies have suggested several candidate genes mapping in different chromosome regions for CL/P malformation. On these grounds, we have investigated, by linkage disequilibrium (LD) and parametric and nonparametric linkage analyses, five different candidate genes, including those for the beta3 subunit of the gamma-aminobutyric acid receptor (GABRB3), glutamic acid decarboxylase 1 (GAD1), retinoic acid receptor alpha (RARA), transforming growth factor beta3 (TGFB3), and msh ( Drosophila) homeobox homolog 1 (MSX1). Interestingly, a significant LD between GABRB3 and CL/P was obtained ( P-value=0.008 in the allele-wise analysis for multiallelic markers), suggesting that the GABRB3 gene is involved in this congenital disease. This new finding in humans is in agreement with previously reported data obtained with the murine model. Indeed, mouse studies indicate a role for gamma-aminobutyric acid (GABA) and its receptor in normal palate development. Exclusion of the GAD1 gene, which encodes the GABA-producing enzyme, in CL/P pathogenesis was obtained in our study. Moreover, we were unable to confirm the involvement of the MSX1 gene in nonsyndromic CL/P. Modest evidence of LD between marker alleles and CL/P was found at the RARA and TGFB3 loci suggesting a minor role for these genes in our family set of nonsyndromic CL/P.

Cleft Lip↗
PubMed1997

Evidence for an association between markers on chromosome 19q and non-syndromic cleft lip with or without cleft palate in two groups of multiplex families.

It has been reported that BCL3 on chromosome 19q, or a nearby gene, may play a role in the etiology of non-syndromic cleft lip with or without cleft palate (NSCL/P) in some families. We tested 30 USA and 11 Mexican multiplex NSCL/P families for four markers on chromosome 19q: D19S178, APOC2/AC1, APOC2/007, and BCL3. While likelihood-based linkage analysis failed to show significant evidence of linkage, the transmission disequilibrium test indicated highly significant deviation from independent assortment of allele 3 at the BCL3 marker in both data sets (USA:P = 0.001; Mexican: P = 0.018; both combined: P < 0.001) and for allele 13 of the D19S178 marker in the Mexican data set (P = 0.004). These results support an association, possibly due to linkage disequilibrium, between chromosome 19 markers and a putative NSCL/P locus.

B-Cell Lymphoma 3 Protein↗
PubMed2000

Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib-pairs.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a complex disorder of multigenic origin involving between two and ten loci. Linkage and association studies of CL/P have implicated a number of candidate genes and regions but have often proved difficult to replicate. Here, we report the findings from a two-stage genome-wide scan of 92 affected sib-pairs to identify susceptibility loci to CL/P. An initial set of 400 microsatellite markers was used, with an average spacing of 10 cM throughout the genome. Eleven regions on eight chromosomes were found to have a P-value smaller than 0.05. These eight chromosomes were then further mapped with a second set of markers to increase the average map density to 5 cM. In seven out of eleven areas densely mapped, significance was markedly increased by decreasing the marker interval. Excessive allele sharing was found at 1p (NPL=2.35, P=0.009, MLS=1.51), 2p (NPL=1.77, P= 0.04, MLS=0.66), 6p (NPL=2.35, P=0.009, MLS=1.34), 8q (NPL=2.15, P=0.015, MLS= 1.51) 11 cen (NPL=2.70, P=0.003, MLS=2.10), 12q (NPL=2.08, P=0.02, MLS= 1.5), 16p (NPL=2.1, P=0.018, MLS=0.97) and Xcen-q (NPL=2.40, P=0.008, MLS=2.68). Although none reached the level required for significant susceptibility loci, two of these areas have previously been implicated in CL/P, viz. 2p13, an area harbouring the TGFA gene, and 6p23-24. We also demonstrate highly suggestive linkage to a susceptibility locus for nonsyndromic clefting on the X chromosome. Further studies are currently underway to replicate these findings in a larger cohort of affected sib-pairs.

Chromosome Mapping↗
PubMed2005

PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses.

The prevalence of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are believed to be higher in the Japanese than in Americans, Europeans or Africans. The purpose of this study was to investigate, in a Japanese population, relationships between CL/P or CPO and seven candidate genes (TGFB3, DLX3, PAX9, CLPTM1, TBX10, PVRL1, TBX22) that showed positive associations in other populations and are expressed in the oral/lip region in developing mice. We first searched for mutations in these genes among 112 CL/P and 16 CPO patients, and found a heterozygous missense mutation (640A > G, S214G) in exon 3 of PAX9 in two sibs with CL/P and their phenotypically normal mother from a Japanese family. A population-based case-control analysis and a family-based transmission disequilibrium test (TDT), using single nucleotide polymorphisms (SNPs), and two-SNP haplotypes of the genes, between the 112 CL/P cases with their parents and 192 controls indicated a significant association at one SNP site, IVS1 + 5321, in TGFB3 with a P-value of 0.0016. Population-based haplotyping revealed that the association was most significant for haplotype "A/A" consisting of IVS1 + 5321 and IVS1 - 1572; TDT also gave a P-value of 0.0252 in this haplotype.

Amino Acid Sequence↗
PubMed2002

Lack of evidence for a significant association between nonsyndromic cleft lip with or without cleft palate and the retinoic acid receptor alpha gene in the Japanese population.

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is one of the most common craniofacial malformations. Both genetic and environmental factors are thought to be involved in the pathogenesis. The retinoic acid receptor alpha ( RARA) is one of the candidate genes for the pathogenesis of NSCLP. An association between a PstI restriction fragment length polymorphism or D17S579 microsatellite marker polymorphism of the RARA gene and NSCLP was previously suggested, but no nucleotide change that may influence the gene expression or the protein sequence has been reported to date. To investigate the possible association between the RARA gene and NSCLP in Japanese patients, we performed a transmission disequilibrium test (TDT) using three microsatellite markers at the RARA locus in 48 parent-offspring trios. The allele-wise TDT did not show evidence of an association between the RARA gene and NSCLP. We also screened nucleotide changes in eight patients with family histories using exon-by-exon direct sequencing. We found a novel nucleotide change (1161C>T) that is located in exon 1 of the RARA gene in one patient whose father also had the disease. Because the 1161C>T was inherited from the patient's healthy mother, the mutation was not considered to be responsible for NSCLP. We then screened all probands for the nucleotide changes in the promoter region of the RARA gene using denaturing high-performance liquid chromatography. A novel nucleotide length polymorphism of a thymidine tract was identified in three patients. No association between this polymorphism and NSCLP was observed. Our findings suggest that the RARA gene variations do not contribute to the development of NSCLP in the Japanese population.

Alleles↗
PubMedDate not supplied

Genetics of nonsyndromic cleft lip with or without cleft palate: is there a Mendelian sub-entity?

The mode of inheritance of nonsyndromic cleft lip with or without cleft palate (NSCLP) is still a matter of dispute. We performed segregation analysis on three data sets of families ascertained through an affected child with NSCLP. The first two data sets were selected in France and were pooled for a global analysis. No major gene effect could be evidenced in spite of a very large number of families (666 pedigrees including 719 nuclear families). The third data set was British and consisted of three-generation families including the offspring of probands. A major gene effect, as well as a strong residual multifactorial component, were highly significant and we could show that this evidence almost entirely came from the information on probands' offspring. We conclude that a mixture of monogenic and of multifactorial cases is probably the best explanation for the observations made in this study. Analyses performed in pedigrees with multiple cases closely related might allow reducing heterogeneity and help identifying those Mendelian sub-entities.

Child↗
PubMed2004

Periconceptional folate intake by supplement and food reduces the risk of nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Inadequate maternal vitamin intake during pregnancy has been suggested as a risk factor for cleft lip with or without cleft palate (CLP). The independent role of folate has not been clarified. METHODS: To investigate the association between maternal folate intake by supplement and food and the risk of CLP offspring, a case-control study was conducted in the Netherlands (1998-2000) among 174 mothers of a child with nonsyndromic CLP and 203 mothers of a child without congenital malformations. RESULTS: Daily use of a folic acid supplement by mothers starting from 4 weeks before until 8 weeks after conception gave a 47% CLP risk reduction compared to mothers who did not use these supplements [odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33, 0.85]. Ninety-three percent of the users took a supplement containing folic acid only. Dietary folate intake reduced CLP risk independently in a dose-response manner. The largest risk reductions were found on those mothers who had a diet of more than 200 microg folate per day in combination with a folic acid supplement (OR: 0.26, 95% CI: 0.09, 0.72). CONCLUSIONS: We demonstrated that periconceptional maternal folic acid supplement use was beneficial to reduce the risk for CLP. An additional effect of food folate was shown.

Adult↗
PubMed1999

Significant association of HLA-B and HLA-DRB1 alleles with cleft lip with or without cleft palate.

Nucleotide sequence level typing of HLA-B, -DRB1, and -DPB1 alleles was performed on Japanese patients with cleft lip with or without cleft palate (CL/P). Two HLA-B alleles, B*1501 and B*5101, showed a significant positive association with CL/P. The increase of B*1501 was evident in female patients (OR=3.6, Pc=0.003), whereas the increase of B*5101 was evident in male patients (OR=3.7, Pc < 0.001). One HLA-DRB1 allele, HLA-DRB1*0802 also showed an increase in CL/P patients. Conversely, HLA-B*4403 and DRB1*1302 were not observed in the patient group (Pc=0.01 and Pc=0.02, respectively). No HLA-DPB1 alleles showed significant association with CL/P. Thus, the present study indicates that HLA alleles, or closely linked loci, may be involved in the pathogenesis of CL/P.

Alleles↗
PubMed2002

Cleft lip with or without cleft palate and dermatoglyphic asymmetry: evaluation of a Chinese population.

OBJECTIVE: To determine if Chinese individuals with non syndromic cleft lip with or without cleft palate (CL/P) display more dermatoglyphic asymmetry than unaffected relatives or controls. DESIGN: Case-control study with two control groups (genetically related and unrelated). SETTING AND SAMPLE POPULATION: A total of 500 CL/P probands from Shanghai, China, 421 unaffected relatives, and 66 controls of Chinese heritage. METHODS: Finger and palm prints were collected, and pattern frequencies, total ridge counts (TRC), and atd angles were calculated. Asymmetry scores between right and left hands were defined for each of the three dermatoglyphic measures. Probands' asymmetry scores were compared statistically with the scores of unaffected relatives and controls. RESULTS: In general, the probands' asymmetry scores for TRC and atd angle did not differ significantly from the scores of either unaffected relatives or controls. However, probands with a positive family history of clefting showed significantly more asymmetry in their pattern types than either probands without a family history, unaffected relatives or controls. CONCLUSION: These results suggest that a unique genetic mechanism of developmental instability may obtain in CL/P individuals with a positive family history of clefting.

Analysis of Variance↗
PubMed2003

Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2.

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.

Chromosome Mapping↗
PubMed2004

Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate.

The 677 C --> T polymorphism in the 5-10 methylenetetrahydrofolate reductase (MTHFR) gene has been associated with nonsyndromic cleft lip with or without cleft palate (CL/P) in some populations, but not others. Previous studies (ie, case-control and transmission disequilibrium tests (TDT)) in Brazilian families with CL/P have been unable to replicate this putative association. However, our group observed a lower proportion of CT heterozygotes among the mothers of CL/P probands, suggesting that the maternal genotype for this polymorphism might influence predisposition to CL/P. In order to further examine this issue, we performed a case-control study of the 677 C --> T/MTHFR polymorphism in families with CL/P ascertained in two regions of Brazil: 172 from São Paulo (SP) and 252 from Ceará (CE). The control samples included 243 individuals from SP and 401 from CE. TDT was carried out in 102 patients with CL/P and their parents. No evidence of an association was observed between the 677 C --> T/MTHFR polymorphism and CL/P using the case-control design, while borderline significance was obtained with the TDT (P=0.055). We have also looked for an interaction between maternal MTHFR genotypes and the propositi offspring's genotypes at two candidate susceptibility loci for CL/P, TGFA and BCL3. Interestingly, we observed an interaction between the maternal MTHFR and offspring's BCL3 genotypes (OR: 2.3; 95% CI: 1.1-4.8; P=0.03) but not with the offspring's TGFA genotypes. Therefore, our results reinforce the idea that the maternal MTHFR genotype plays a significant role in susceptibility to CL/P, but its teratogenic effect depends on the genotype of the offspring.

Adult↗
PubMed2002

Genome scan for loci involved in cleft lip with or without cleft palate, in Chinese multiplex families.

Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly. Birth prevalences range from 1/500 to 1/1,000 and are consistently higher in Asian populations than in populations of European descent. Therefore, it is of interest to determine whether the CL/P etiological factors in Asian populations differ from those in white populations. A sample of 36 multiplex families were ascertained through probands with CL/P who were from Shanghai. This is the first reported genome-scan study of CL/P in any Asian population. Genotyping of Weber Screening Set 9 (387 short tandem-repeat polymorphisms with average spacing approximately 9 cM [range 1-19 cM]) was performed by the Mammalian Genotyping Service of Marshfield Laboratory. Presented here are the results for the 366 autosomal markers. Linkage between each marker and CL/P was assessed by two-point and multipoint LOD scores, as well as with multipoint heterogeneity LOD scores (HLODs) plus model-free identity-by-descent statistics and the multipoint NPL statistic. In addition, association was assessed via the transmission/disequilibrium test. LOD-score and HLOD calculations were performed under a range of models of inheritance of CL/P. The following regions had positive multipoint results (HLOD > or =1.0 and/or NPL P< or =.05): chromosomes 1 (90-110 cM), 2 (220-250 cM), 3 (130-150 cM), 4 (140-170 cM), 6 (70-100 cM), 18 (110 cM), and 21 (30-50 cM). The most significant multipoint linkage results (HLOD > or =2.0; alpha=0.37) were for chromosomes 3q and 4q. Associations with P< or =.05 were found for loci on chromosomes 3, 5-7, 9, 11, 12, 16, 20, and 21. The most significant association result (P=.009) was found with D16S769 (51 cM).

China↗
PubMed2004

Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population.

Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects, but its etiology is largely unknown. It is very likely that both genetic and environmental factors contribute to this malformation. Mutations in the gene for interferon regulatory factor 6 (IRF6) have been shown to be the cause of Van der Woude syndrome, a dominant disorder that has CL/P as a common feature. Recently, it has been reported that genetic polymorphisms at the IRF6 locus are associated with nonsyndromic CL/P, with stronger association in Asian and South American populations. We investigated four markers spanning the IRF6 locus, using the transmission/disequilibrium test. A sample of 219 Italian triads of patients and their parents were enrolled in the study. Strong evidence of linkage disequilibrium was found between markers and disease in both single-allele (P=.002 at marker rs2235375) and haplotype (P=.0005) analyses. These findings confirm the contribution of IRF6 in the etiology of nonsyndromic CL/P and strongly support its involvement in populations of European ancestry.

Cleft Lip↗
PubMed2003

Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate?

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.

Case-Control Studies↗
PubMed1983

Fetal mortality and cleft lip with or without cleft palate.

Analysis of fetal mortality in sibships of 406 probands with cleft lip with or without cleft palate (CL(P)) indicates that the incidence of fetal mortality is significantly greater in sibships of probands with bilateral CL(P) than in those of unilateral CL(P). The difference is even greater when fetal mortality in sibships of male probands with unilateral CL(P) is compared with that of female probands with bilateral CL(P). These findings support a multifactorial two-threshold concept in which a lower level of liability results in clefting while a higher level of liability causes fetal mortality.

Cleft Lip↗
PubMed2004

Myo-inositol, glucose and zinc status as risk factors for non-syndromic cleft lip with or without cleft palate in offspring: a case-control study.

OBJECTIVE: To investigate myo-inositol, glucose and zinc status in mothers and their infants on cleft lip with or without cleft palate risk (CLP). DESIGN: Case-control study. SETTING: University Medical Centre Nijmegen, the Netherlands. POPULATION: Eighty-four mothers and their CLP child and 102 mothers and their healthy child. METHODS: Venous blood samples were obtained to determine serum myo-inositol and glucose and red blood cell zinc concentrations in mothers and children. Geometric means were calculated and compared between the groups. The blood parameters were dichotomised with cutoff points based on control values, P90 for glucose concentrations. MAIN OUTCOME MEASURES: Geometric means (P5-P95) and odds ratios (95% confidence intervals). RESULTS: The CLP children (P= 0.003) and their mothers (P= 0.02) had significantly lower red blood cell zinc concentrations than controls. A low maternal serum myo-inositol concentration (<13.5 micromol/L) and a low red blood cell zinc concentration (<189 micromol/L) increased CLP risk [odds ratio 3.0 (95% CI 1.2-7.4) and 2.0 (95% CI 0.8-4.8), respectively]. Children with low myo-inositol (<21.5 micromol/L ) or low red blood cell zinc concentrations (<118 micromol/L) were more likely to have CLP [odds ratio 3.4 (95% CI 1.3-8.6) and 3.3 (95% CI 1.3-8.0), respectively]. Glucose was not a risk factor for CLP in mothers and children. Maternal and child myo-inositol as well as zinc concentrations were slightly, albeit significantly correlated, r(Pearson)= 0.33 (P= 0.0006) and r(Pearson)= 0.23 (P= 0.01), respectively. CONCLUSION: This study demonstrates for the first time that zinc and myo-inositol are important in the aetiology of CLP.

Adult↗
PubMed2006

Parental craniofacial morphology in cleft lip with or without cleft palate as determined by cephalometry: a meta-analysis.

OBJECTIVE: To integrate findings from previous cephalometric studies comparing the craniofacial complex of unaffected parents with cleft lip with or without cleft palate (CL/P) children to controls with no history of the disease. DESIGN: Meta-analysis of case-control cephalometric data. INCLUSION CRITERIA: Studies were selected if the unaffected parents of children with CL/P were included and were not combined with parents of children with isolated CP; quantitative data were obtained through cephalometry; the cephalometric variables used were not unique to a study; a case-control design was used; and the means and standard deviations for all variables were reported or could be calculated for both the experimental and the control group. OUTCOME MEASURE: Using raw data obtained from nine studies, mean weighted effect sizes with 95% confidence intervals were calculated for 28 cephalometric variables (mothers and fathers combined) or 18 variables (mothers and fathers separately). Heterogeneity statistics for the effect sizes were also calculated. RESULTS: In general, unaffected parents of children with CL/P possessed significantly wider interorbital, nasal cavity and upper facial dimensions, narrower cranial vaults, longer cranial bases, longer and more protrusive mandibles, shorter upper faces and longer lower faces compared with controls. Increased width of the nasal cavity was the most robust finding. Significant effect size heterogeneity was observed in roughly half of the variables examined. CONCLUSION: Unaffected parents of children with CL/P are characterized by a suite of consistent, yet subtle, craniofacial differences, which could indicate an underlying genetic liability.

Case-Control Studies↗
PubMed2005

Significant association between IRF6 820G->A and non-syndromic cleft lip with or without cleft palate in the Thai population.

BACKGROUND: Previous data have shown an association between DNA sequence variants in the IRF6 gene and an increased risk of non-syndromic cleft lip with or without cleft palate (CL/P) in some populations. OBJECTIVE: To investigate Thai CL/P patients and relative for a 820G-->A polymorphism. SUBJECTS: 192 CL/P Thai patients, 177 of their mothers, 73 of their fathers, and 278 controls. RESULTS: There were significant differences in the frequency distributions of both genotypes (p = 0.02) and alleles (p = 0.04) among probands as compared with the control group. The odds ratio calculated for the patients having the GG genotype compared with the other two genotypes (GA and AA) was 1.67 (95% confidence interval, 1.13 to 2.47). This pattern is consistent with a recessive effect of the G allele. No association between any of the parents' genotypes and CL/P was found. The IRF6 820G-->A was responsible for 16.7% of the genetic contribution to CL/P. CONCLUSIONS: The findings confirm that IRF6 820G-->A is associated with CL/P.

Cleft Lip↗