Indian Journal of Plastic Surgery
An open access publication of Association of Plastic Surgeons of India
Users Online: 198  
Home | Subscribe | Feedback | Login 
  Navigate here 
 ╗  Next article
 ╗  Previous article 
 ╗  Table of Contents
 Resource links
 ╗   Similar in PUBMED
 ╗  Search Pubmed for
 ╗  Search in Google Scholar for
 ╗Related articles
 ╗   Article in PDF (167 KB)
 ╗   Citation Manager
 ╗   Access Statistics
 ╗   Reader Comments
 ╗   Email Alert *
 ╗   Add to My List *
* Registration required (free)  
  In this article
   Linkage Studies
   Genome-Wide Screens
   Association Stud...
   Contribution of ...
   Animal Models
   Genetic Predispo...
   Folic Acid
   Article Tables

 Article Access Statistics
    PDF Downloaded539    
    Comments [Add]    
    Cited by others 19    

Recommend this journal


Year : 2009  |  Volume : 42  |  Issue : 1  |  Page : 68-81

Current concepts in genetics of nonsyndromic clefts

1 Department of Plastic Surgery, Sri Ramachandra Medical College, Chennai, India
2 Department of Biomedical Sciences, Sri Ramachandra Medical College, Chennai, India

Date of Web Publication29-Jun-2009

Correspondence Address:
Jyotsna Murthy
Department of Plastic Surgery, Sri Ramachandra University, Chennai - 600 116
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-0358.53004

Rights and Permissions

 ╗ Abstract 

Nonsyndromic cleft lip and palate is a complex genetic disorder with variable phenotype, largely attributed to the interactions of the environment and multiple genes, each potentially having certain effects. Numerous genes have been reported in studies demonstrating associations and/or linkage of the cleft lip and palate phenotypes to alleles of microsatellite markers and single nucleotide polymorphisms within specific genes that regulate transcription factors, growth factors, cell signalling and detoxification metabolisms. Although the studies reporting these observations are compelling, most of them lack statistical power. This review compiles the evidence that supports linkage and associations to the various genetic loci and candidate genes. Whereas significant progress has been made in the field of cleft lip and palate genetics in the past decade, the role of the genes and genetic variations within the numerous candidate genes that have been found to associate with the expression of the orofacial cleft phenotype remain to be determined.

Keywords: Cleft; Genetics; Nonsyndromic clefts

How to cite this article:
Murthy J, Bhaskar L. Current concepts in genetics of nonsyndromic clefts. Indian J Plast Surg 2009;42:68-81

How to cite this URL:
Murthy J, Bhaskar L. Current concepts in genetics of nonsyndromic clefts. Indian J Plast Surg [serial online] 2009 [cited 2019 Jul 16];42:68-81. Available from:

 ╗ Introduction Top

Cleft lip and cleft palate are birth defects that affect the upper lip and roof of the mouth. It is the most common disease affecting children with variable phenotype. Some babies have only a cleft lip and many babies with cleft lip have a cleft palate as well. Cleft palate also can occur by itself without cleft lip (isolated cleft palate). Cleft lip/palate (CL/P) and isolated cleft palate are considered separate birth defects. Approximately 70% of CL/P cases are nonsyndromic occurring as an isolated condition unassociated with any recognizable anomalies, while the remaining 30% are of syndromic cases present in association with deficits or structural abnormalities occurring outside the region of the cleft. [1] Nonsyndromic CL/P is a common craniofacial malformation with a complex genetic component. From the available literature it can be seen that the incidence of orofacial clefting varies depending on geographical location, ethnicity, sex and even socioeconomic status. The incidence of CL and CLP is higher than CP. Incidence also varies markedly in different ethnicities. Though methods of ascertaining and classification criteria can influence incidence rates, it reported that North American Indians and Asians have the highest prevalence rates (sometimes as high as 1 in 500), while Caucasian populations have intermediate rates (1 in 1000) and African derived populations have the lowest prevalence rates (1 in 2500). Among the Asians the Japanese are believed to have the highest rates. The prevalence in Latino Americans is lower than that in Caucasians and Native Americans, yet it is still higher than African Americans. The frequency of CLP/ CP differs with regard to sex and side of clefting with 2:1 (male:female) ratio and a 2:1 (left side:right side) ratio for clefting in unilateral clefts. Cleft palate alone (CP) results in a prevalence rate of 5.5 to 6.6 per 10,000 births approximately and has a 0.73:1 (male: female) ratio among the Caucasian population.

Many sub-phenotyping features related with nonsyndromic cleft lip and palate have been studied, such as handedness, dental anomalies and dermoglyphic features. To date several studies have reported higher incidence of non-right-handedness in nonsyndromic CL/P but the specific nature of this relationship remains unclear. The results on the relationship between dermatoglyphic patterns and nonsyndromic cleft lip and palate have been fairly consistent. However, cleft lip and palate individuals seem to be characterized by an increased frequency of arches and ulnar loops and a decreased frequency of whorls. Orbicularis oris muscle defects are informative subclinical indicators of increased susceptibility to CL/P because preliminary studies have shown that the orbicularis oris muscle is hypoplastic in first-degree relatives of CL/P individuals than in controls. Many dental anomalies are associated with CL/P, ranging from a single malformed tooth in the vicinity of the cleft to dentition-wide reductions in tooth size or multiple congenitally missing teeth in both arches.

Multiple environmental factors are known to trigger and/ or modulate the cleft formation. The genetic components of cleft that underlie the susceptibility to respond to the environment still remain largely indefinite. Because of myriad of mendalian patterns exhibiting varying levels of penetrance, sex differences and environmental overlays, gene identification is difficult. [2] However, the current understanding of its complex nature supports the concept that nonsyndromic clefts are attributed to multiple interacting genes, with their own variable tendency to be expressed. [3],[4],[5] In addition, these disorders require the presence of appropriate environmental triggers for their expression. Although both physiologic/pharmacologic and genetic studies in animal models and human populations have identified several candidate genes and pathways that regulate transcription factors, growth factors, cell signalling and detoxification metabolisms, [6],[7] the significance to nonsyndromic clefts of genetic variations such as single nucleotide polymorphisms (SNPs) in these genes is still unconfirmed.

Several genome-wide scans for nonsyndromic clefts and their associated or related traits have been carried out. [8],[9],[10] Most of these studies lack sufficient statistical power, and also they are not consistent in reporting genetic linkage to the same chromosomal region. The genes responsible for one form of X-linked ( CPX [MIM 303400]) and one form of autosomal dominant ( CPI [MIM 119530]) CL/P have been mapped to Chromosomes Xq13-q21.31 [11],[12] and 2q32 [13] respectively. Pathogenic mutations were identified in the TBX22 gene on Xq21.1. Genomic regions with evidence of linkage for nonsyndromic orofacial cleft (NSOFC) were identified at 6p24-p23 ( OFC1 [MIM 119530]), [14],[15],[16] 2p13 ( OFC2 [MIM 602966]), [8],[17],[18] 19q13 ( OFC3 [MIM 600757]), [18],[19] 4q21-q31 ( OFC4 [MIM 608371]), [8],[20] 4q16 ( OFC5 [MIM 608874]), [21],[22],[23] 1q32.3-q41 ( OFC6 [MIM 608864]), [24],[25] 11q23.3 ( OFC7 [MIM 600644]), [26],[27] 3q28 (OFC8 (603273)), [28],[29] 13q33.1-q34 (OFC9 (610361)) [9] and 2q33 (OFC10 (601912)), [30] but not all responsible genes are yet identified. Chromosomal aberrations involving Chromosomes 13 and 18 were reported to cause an increased incidence of clefts. [31]

Furthermore, disease-contributing alleles may also be present in genes for the MSX2, RARA, TGFA, TGFB3, TGFB2, MTHFR, GABRB3, FOXE1, GLI2, JAG2, LHX8, PHF8, SATB2, SKI, SPRY2, and TBX10. [22],[32] However, none of these seem to play a major role in nonsyndromic CL/P, and they appear to be responsible for only a fraction of CL/P cases. [22] Most of these chromosomal regions contain more than one susceptibility locus for nonsyndromic clefts. Other linkage regions do not contain palpable candidate genes.

We performed a MEDLINE literature search by means of specific search terms ('cleft lip', 'cleft palate', 'candidate genes', 'single nucleotide polymorphisms', 'aetiology', and 'genetics') to identify relevant articles, primarily focusing on studies published till October 2008. The results summarize the latest information regarding the role of genetic influences in the development of nonsyndromic clefts and reflect our current information on some of the best-known genes that potentially contribute to the formation of clefts.

 ╗ Linkage Studies Top

Linkage analysis tests for cosegregation of a gene marker and disease phenotype within a family, to determine if the marker and the disease gene are physically linked. An array of family configurations can be tested, such as multiplex extended pedigrees and nuclear families with affected sib-pairs. Linkage studies have revealed at least 20 contributing chromosomal regions. [33] Scapoli et al. [34] found significant linkage disequilibrium between the GABRB3 gene and CL/P. Evidence for linkage to Chromosome 1p near the 5,10-methylenetetrahydrofoalte reductase locus and in the 1q21 and 1q32-42.3 regions has been reported for CL/P. [35] Regions on Chromosomes 6p, 2p, 4q and 17q have all shown some evidence of linkage to CL/P. [36] Beiraghi et al. [37] found linkage to 4q in one family and Mitchell et al. [38] showed evidence of association to this same region, but a later study showed evidence against linkage in this region. [39] Pezzetti et al. [40] reported a possible interaction between two regions that mapped in 6p23 and 2p13 in 38 CL/P multiplex families from Italy. However, Wong et al . [41] studied Swedish multiplex CL/P families, and found no evidence of linkage to selected candidate genes on Chromosomes 2, 4, 6 or 19. Similarly, Marazita et al . [8] did not find significant linkage in any of these regions in 36 CL/P multiplex Chinese families. Stein et al . [42] found significant linkage with BCL3 on Chromosome 19q in a fraction of their families. Wyszynski et al. [18] and Martinelli et al. [43] failed to find further evidence of linkage to this marker, but they did find a significant association for an allele at this marker using the transmission disequilibrium test (TDT).

 ╗ Genome-Wide Screens Top

Prescott et al. [15] first reported linkage of a genome-wide significance with two-stage genome-wide scan, using 92 UK sib pairs of CL/P, identified 11 loci on eight chromosomes using the 10-cM mapping in the first stage and seven of these loci were confirmed by a 5-cM mapping panel in the second stage. These eight chromosomal regions were on chromosomes: 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) 11cen (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. However, the statistical methods applied and the calculated P values have been criticized for not being stringent enough to support a genome-wide level of statistical significance. This is not surprising in view of the low genetic power expected from the study of 92 affected sibling pairs. The genome scan on Chinese multiplex families revealed positive multipoint results for regions on Chromosomes 1, 2, 3, 4, 6, 18 and 21 with the most significant results (HLOD = 2.0; a = 0.37) at 3q26 and 4q21. [8] Genome-wide scan of two large Syrian families detected a significant LOD score of 3.0 at 17p13.1. [44] Genome-wide scan on 10 multiplex families of Mexico, Argentina, and the United States yielded suggestive evidence of linkage to Chromosomes 2, 6, 17 and 18. Subsequent Fine mapping analysis showed intriguing evidence of linkage to 2q. [45] Field et al. [46] reported statistically significant two-point linkage results with markers on Chromosome 7 (LOD = 1.89), Chromosome 5 (LOD = 1.76), Chromosome 15 (LOD = 1.55), and Chromosome 20 (LOD = 1.46) in a genome-wide scan on 38 CL/P multiplex families of West Bengal. The linkage genome scan among 18 consanguineous CL/P Turkish families yielded statistically significant multipoint results from and regions on Chromosomes 4, 10, 12, and 15 with maximum multipoint HLOD's of 1.25, 1.30, 2.73, and 1.28 respectively. [47] Given that each individual study lacks statistical power for confirmatory linkages, various attempts have been made, using the method of meta-analysis, to combine the evidence from several studies on multiple markers in a particular candidate region and to summarize the multipoint LOD values evaluated at the location of each marker. However, this is not always practical because of the variability in methods and models between different studies. Marazita et al. [48] presented a meta-analysis of 13 10-cM genome scans of 388 extended multiplex families with CL/P from seven diverse populations (genotyped 2,551 individuals). The combination of evidence over multiple samples from 388 families, pinpointed highly significant loci contributing to nonsyndromic cleft lip and palate susceptibility with a maximum heterogeneity LOD score 6.6 near 9q21 and another (2q32-35) had a meta-analysis P value of 0.0004. A recent nonparametric linkage (NPL) analysis of two Indian pedigrees identified 11 genomic regions that could potentially harbour CL/P susceptibility variations with most significant evidence of linkage for Chromosome 13q33.1-34 at marker rs1830756 with heterogeneity LOD score of 5.57 [9] and significant evidence of linkage for marker rs728683 on Chromosome 18q21.1 with LOD of 3.97 was identified that most likely harbours a high-risk variant for CL/P. [10] To determine statistical significance in genome-wide scans many laboratories use LOD > 3.7 and P < 2 Î 10-5. [49] It is noteworthy that few of the genome-wide scans performed to date on nonsyndromic clefts could not meet the Lander and Kruglyak criteria [49] because of insufficient information content of the mapped locus ( i.e. marker interval more than 1.5 cM). The small deletions or duplications of chromosome material can lead to orofacial clefts. Array-CGH has been developed as a method to identify and map sub-microscopic deletions/duplications simultaneously onto the genome sequence. The use of multiple probes simultaneously is now possible using probes of known location on the genome 1 Mb apart. Recent studies using array comparative genomic hybridization helped in identifying the novel candidate genes associated with cleft lip and palate. [50],[51]

 ╗ Association Studies Using Single Nucleotide Polymorphisms Top

Association studies determine whether alleles occur together with a specific phenotype more often than in a control group. This was done most commonly by associating nonsyndromic cleft lip or palate to microsatellite markers or SNPs within specific transcription factors, growth factors, cell signalling and detoxification metabolisms regulating genes. A specific allele has to be suspected as disease-causing or protective and therefore tested in either a case-control study or a family-based association design. Clues towards candidate genes typically originate from basic biological studies such as animal models. Association studies provide a powerful tool for identifying alleles of minor importance. In this regard, using the case-control design, Ardinger et al. [17] found an increased risk for CL/P among cases carrying the Taq1 C2 allele of the TGFA gene (OR = 3.18, 95% CI = 1.26 to 8.22). These results were later confirmed by two other small case-control studies: Holder et al . [52] and Sassani et al . [53] found an association between CL/P and the Taq1 C2 allele (Chi-square = 15.04, 1 df , P = 0.001 and Chi-square = 5.08, P = 0.02, respectively). Mitchell [54] performed a meta-analysis utilizing results from all available studies throughout the year 1997 and found a statistically significant overall association between CL/P and TGFA genotype (OR 5 1.43, 95% CI 5 1.12 to 1.80). Romitti et al . [55] did not find evidence that the C2 allele at TGFA increased risk for either CL/P (OR 5 0.9, 95% CI 5 0.5 to 1.5) or CP (OR 5 1.0, 95% CI 5 0.4 to 2.0) in a case-control study from Iowa. A false association may be detected if the tested variant is not the actual disease-causing variant, but closely located to the disease-causing variant. False associations may also occur if the case and control groups show differences in the studied allele frequencies, not causally related to the studied disease, i.e. population stratification. [56] Because of the risk of population stratification, family-based association designs have become increasingly popular. A key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24 was identified in a genome wide association study. [57] Case-control association studies have provided evidence that variants in the genes MTHFR, ARNT, TGFA, GAD1, MSX1, RARA, TGFB3 are associated with the CL/P phenotype. Several studies using candidate genes involved in pathways that regulate transcription factors, growth factors, cell signalling and detoxification metabolisms are represented in [Table 1].

Recent technical progress has made it possible to perform high-throughput sequencing of candidate genes in large patient cohorts. Not only genes identified in syndromic CL/P, but also candidates selected on the basis of animal studies, linkage and cytogenetic studies have now been sequenced. [22] This may increase the number of genes known to contribute to CL/P substantially, but we still have important work to do in the field of biological causality.

 ╗ Contribution of Syndromes Associated with OFC Top

Clefts associated with other syndromes also had given sufficient hints to map the genes underlying the isolated forms. [58] More than 300 syndromes are known to have either cleft lip or palate as an allied feature ( One of the most common autosomal dominant disorders associated with CLP is Van derWoude syndrome (VWS) (OMIM 119300), associated with highly characteristic pitting of lower lip mucosa and CLP. [59] The locus for VWS has previously been mapped to Chromosome 1 (1q32-q41). [60] Recently, mutations in the interferon regulatory factor 6 (IRF6) gene were reported to underlie VWS, [60],[61] and, subsequently, variants in IRF6 were found to be significantly associated with nonsyndromic clefting as well. [24],[62] A recent study identified a mysterious SNP rs642961, in a previously unexplored enhancer region of the IRF-6 gene causing about 18 percent of CP malformation. [63] The Wolf-Hirschhorn syndrome (WHS) (OMIM 194190) , caused by partial deletion of the short arm of Chromosome 4 (4p), is characterized by severe growth retardation and mental defect, microcephaly. The craniofacial abnormalities include microcephaly, maxillary hypoplasia, hypertelorism, high nasal bridge with a characteristic Greek warrior helmet appearance, oral clefts, and dental anomalies. [64] Fluorescence in situ hybridization (FISH) analysis of eight Finnish patients with WHS was done; five patients lacked one copy of MSX1 with oligodontia, while the other three had two hybridization signals. One of these presented with the only case of cleft palate. [65] A heterozygous MSX1 nonsense mutation has been identified in a three-generation Dutch family exhibiting various combinations of CLP, CP and selective tooth agenesis. [66] In a follow-up study using 1000 unrelated individuals with CLP, complete sequencing of the gene showed that mutations in MSX1 alone could account for 2% of isolated CL/P. [32]

Autosomal dominant form of Kallmann syndrome (KAL2) (OMIM 147950), which is characterized by hypogonadism and anosmia, and also clefting in 5-10% of the cases is caused by mutation in the gene encoding fibroblast growth factor receptor-1. [67] FGFR1 (fibroblast growth factor receptor-1), encodes a transmembrane receptor tyrosine kinase that transduces signals from secreted FGFs. [68] Dode et al . [69] confirmed that loss-of-function mutations in FGFR1 account for approximately 20% of all cases of Kallmann syndrome. Recent analysis of 12 genes involved in the fibroblast growth factor signalling pathway in nonsyndromic cleft lip or palate families revealed seven mutations in which structural analysis predicted functional impairment in the FGFR1, FGFR2, FGFR3, and FGF8 genes and causing 3 to 5% of nonsyndromic cleft lip or palate. [70] Cleft lip/palate ectodermal dysplasia syndrome (CLPED) is characterised by cleft lip with or without cleft palate, hidrotic ectodermal dysplasia, syndactyly, and occasionally mental retardation. The inheritance of CLPED appears to be autosomal recessive. Other syndromes such as Zlotogora-Ogur syndrome and Margarita Island ectodermal dysplasia are also classified as CLPED. Using positional cloning, Suzuki et al . [26] identified mutations of the poliovirus receptor like-1 gene ( PVRL1 ) in CLPED families from Margarita Island, Israel, and Brazil. A non-sense mutation of PVRL1 gene ( W185X) is a susceptible allele in clefting in Northern Venezuela and was not found in any of the nonsyndromic cleft populations. [71] Later, a study using 146 CLP patients and 100 unaffected individuals of Italian origin did not find the W185X mutation in any samples. [72] A common glycine allele of the G361V polymorphism was significantly over-transmitted among all orofacial clefting phenotypes in all Iowan, Danish, and Filipino families. [73] Many other syndromes which have the cleft as one of the allied abnormalities have given several hints to identify the genes such as TP63 (OMIM 603273; 3q27), [74] TBX22 (OMIM 300307; Xq12-q21), [75],[76] FOXC2 (OMIM 602402; 16q24.3), [77],[78] FOXE1(OMIM 602617; 9q22). [79]

 ╗ Animal Models Top

The mouse model is the preferred mammalian animal model, because it has a short reproduction cycle and a known genomic sequence, very close to the human genomic sequence. [80] Many genetically manipulated mouse models such as knockout, knock-in, gene-trapped, spontaneous mutations and chemically induced mutations provided an excellent opportunity to study CL/P. Many CL/P mouse models have counterparts in syndromic CL/P forms found in humans. Animal models with clefts arising spontaneously or as a result of mutagenesis experiments provide another exciting avenue for gene mapping. [81] Indeed, studies in these animal models have helped to identify a series of genes essential for palatal formation. Endothelin-1 (EDN1) is synthesized by vascular endothelial cells and is found in plasma. EDN1 is released from an inactive transitional form in a step catalyzed by endothelin-converting enzyme (ECE). EDN1 knockout mice have shown craniofacial abnormalities, including cleft palate. [82] The mouse deficient in ECA or in endothelin-A receptor genes also has shown almost identical abnormalities to those of EDN1-deficient mice. [83] Whereas in zebra fish, EDN1 is expressed ventrally in the primordia of the pharyngeal arches and helps in patterning of pharyngeal cartilage development. By injecting the morpholino, Kimmel et al . [84] have demonstrated the role of EDN1 in the sizing of pharyngeal skeletal elements of the jaw and opercular regions in zebra fish. But genes involved in the endothelin pathway (EDN1, ECE1, EDNRA, EDNRB) have not shown linkage with orofacial clefts. [85] γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system. Mice homozygous for mutations in the GABA synthesizing enzyme Gad67 indicate a role for GABA function in the development of the palate. [86],[87] Similarly, mice lacking TGF-beta 3 exhibit an incompletely penetrant failure of the palatal shelves to fuse, leading to cleft palate. [88] The Msx1 homeobox gene is expressed at diverse sites of epithelial-mesenchymal interaction during vertebrate embryogenesis, and has been implicated in signalling processes between tissue layers. Mice lacking Msx1 function manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. [89],[90]

 ╗ Genetic Predisposition to Environmental Factors Top

Since the first report on the possible involvement of the environmental component in clefting, [91] extensive screening for teratogens that cause clefts has been conducted. A genetic predisposition has long been observed. A foetus with an affected parent or sibling has a 2-4% risk for a development of oral cleft compared to the 0.15% risk for the general population. Anti-epileptic medications taken in pregnancy have been shown to be associated with oral clefts; and other environmental factors are suspected, including maternal smoking, heavy alcohol intake, infections, folic acid deficiency, and Vitamin A toxicity. [92],[93]

 ╗ Stress Top

Previous studies revealed increased risk of clefts among infants born to women with higher stress. [94],[95] It has been hypothesized that maternal stressors may cause birth defects through increased production of corticosteroids. Animal studies in rodents and rabbits have demonstrated that high doses of corticosteroids consistently cause cleft palate. [93],[94],[96] Stressful life events have been shown to be associated with increased levels of maternal corticotrophin-releasing hormone and corticosteroid during pregnancy. [97],[98] Increased risk of oral clefts was observed in the infants born to women who took corticosteroid medications during the first trimester of pregnancy. [99],[100]

 ╗ Smoking Top

Cleft lip and cleft palate is one of the congenital defects associated with maternal smoking. As early as 1979, Ericson et al. [101] found an association between smoking and oral clefts. Cigarette smoking during pregnancy was associated with cleft defects. [102],[103] In contrast, some studies found no association with maternal smoking for any form of oral clefts. [55],[104] Meta-analysis of 11 published studies revealed an overall odds ratio of 1.29 (95% CI= 1.18 to 1.42) for any oral cleft in children of women who smoked. [105] When maternal smoking was considered together with a certain genetic background, the combined effect was more significant. The maternal glutathione s-transferase q-1 ( GSTT1 ) genotype, combined with smoking, could significantly increase the risk of CLP with an odds ratio of 4.9. [106] Infant MSX1 genotypes in combination with maternal smoking contributed to an elevated risk for CLP by 7.16 times. [107] Moreover, use of multivitamins also did not mitigate the risk of oral clefting associated with smoking.

 ╗ Alcohol Top

Seminal studies revealed the teratogenic effects of heavy alcohol exposure. [108] Abel [109] reported that 9-18% of infants with foetal alcohol syndrome possess cleft lip with or without cleft palate. Alcohol consumption during pregnancy was associated with cleft defects. [55],[110] Low-level alcohol consumption, however, did not seem to increase the risk of orofacial clefts. [111] A recent population-based case-control study showed that even a low level of alcohol consumption during pregnancy was significantly associated with an elevated risk of orofacial clefts in the offspring. [112] The child carrying mutant ADH1C allele seems to have a protective effect against the risk of oral clefts, but the maternal genotype plays a less important role than the child's genotype. [113] CYP2E1 genotypes of mother and child showed reduced risks of nonsyndromic oral cleft in children carrying the CYP2E c1/c2 mutated allele. [114]

 ╗ Folic Acid Top

Maternal nutrition may act as a forecast for the foetus of the nutritional environment it will encounter after birth. Maternal nutrition during pregnancy also appears to play an important role in palate development. Palate development delay was observed in folic acid-deficient mice. [115] Low dietary intake of B-complex vitamins and exposure to deficient or excessive amounts of vitamin A, have been linked to increased risks of clefts. Methylenetetrahydrofolate reductase (MTFHR) catalyzes the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is a co-substrate for remethylation of homocysteine to methionine. Methylenetetrahydrofolate reductase deficiency leads to homocystinuria. Significantly higher serum homocysteine levels were detected in mothers of babies with OFC compared with mothers of unaffected babies. [116],[117] It has also been hypothesized that genetic variants in the enzymes controlling folate metabolism might play a role in the susceptibility of oral clefts. The gene encoding the MTHFR enzyme is known to have at least two functional polymorphisms: C677T and A1298C . The C677T variant of the gene encoding the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme affects folate status. Compared with homozygotes (CC) for the common MTHFR C677T variant, heterozygotes (CT) have been reported as having 65% of enzyme activity levels in vitro and 30% of homozygous variants (TT). [118] The results of investigations of the presence of the MTHFR C677T variant in the mother and CLP have been inconsistent. The results of both the case-control comparison and the family-based transmission disequilibrium test analysis revealed no association of the MTHFR 677TT genotype or the 677T allele with CLP. [3],[119],[120] A few studies have shown statistically significant positive associations between 677TT genotype and OFCs. [121] Wilcox et al. [122] reported that at least 400 Ág/day of folic acid supplementation during early pregnancy was significantly associated with reduced risk of cleft lip even after adjustment for multivitamins, smoking, and other potential confounding factors.[156]

 ╗ Conclusions Top

There is strong evidence that nonsyndromic orofacial clefts have genetic predisposition, but in the absence of a classic mendelian inheritance pattern. The orofacial clefts are caused by the interactions of multiple interacting genes, each gene having its own variable tendency to be expressed. In addition, the expression of orofacial clefts requires the presence of appropriate environmental triggers. Markers in more than 16 chromosomal regions have shown evidence of linkage to orofacial clefts or its related phenotypes in many genome-wide studies, suggesting that these genetic loci may contain major genes influencing the expression of orofacial clefts. These include, but are not exclusive to or limited to, genes that regulate transcription factors, growth factors, cell signalling and detoxification metabolisms. However, it remains to be determined whether polymorphisms in these genes account for the reported linkages in these regions. Studies are under way in many laboratories around the world to identify the disease-causing variations in these genes that account for the linkages discussed above. Although no major gene has been confirmed, it is noteworthy that the field of cleft palate genetics has evolved in a relatively short time into a research field. If successful, the genetic approach is likely to provide a new plane of understanding on the pathophysiology of the orofacial clefts. It is, however, clear that there is no single major genetic risk factor for the development of orofacial clefts; and the development of the orofacial clefts in an individual will depend on the interaction of several genes of moderate effect with environmental factors. Identifying specific genetic polymorphisms that influence orofacial cleft phenotypes will shed light on the molecular pathways involved in these complex disorders and provide a better understanding of the pathophysiology of orofacial clefts.

 ╗ Glossary Top

Allele: An alternative form of a gene (a viable DNA) that is located at a specific position on a specific chromosome. Usually alleles are sequences that code for a gene, but sometimes the term is used to refer DNA sequence variants in non-functional or junk DNA. In a diploid organism, one that has two copies of each chromosome, two alleles make up the individual's genotype. An individual's genotype for that gene is the set of alleles it happens to possess. Different alleles and their combinations may result in different phenotypes.

Association studies: Genetic association studies assess correlations between genetic variants and disease phenotypes on a population scale, relying on linkage disequilibrium between genotyped markers and unknown disease loci.

Candidate gene: Any gene that is suspected of being involved in a disease. The gene may be a candidate because it is located in a particular chromosome region suspected of being involved in the disease or its protein product may suggest that it could be the disease gene in question. A candidate gene can also be identified by association with the phenotype and by linkage analysis to a region of the genome.

Chromosome: The DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes in diploid organisms such as humans come in pairs; each member of a pair is inherited from one of the parents. Humans carry 23 pairs of chromosomes and are not visible even under microscope. Chromosomes can be distinguished by their length and by their banding pattern when stained with appropriate methods. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or "arms." The short arm of the chromosome is labeled the "p arm." The long arm of the chromosome is labeled the "q arm." The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.

Codon: A set of three adjacent nucleotides, also called triplet, in mRNA that base-pair with the corresponding aniticodon of tRNA molecule that carries a particular amino acid, hence, specifying the type and sequence of amino acids for protein synthesis. All 64 possible 3-letter combinations of the DNA coding units T, C, A and G are used either to encode one of these amino acids or as one of the three stop codons that signals the end of a sequence. While DNA can be decoded unambiguously, it is not possible to predict a DNA sequence from its protein sequence. Because most amino acids have multiple codons, a number of possible DNA sequences might represent the same protein sequence.

Complex traits: Complex traits are features whose properties are controlled by many genes. These are also known as polygenic traits. Polygenic inheritance, also known as quantitative or multi-factorial inheritance refers to inheritance of a phenotypic characteristic that is attributable to two or more genes and their interaction with the environment. Unlike monogenic traits, polygenic traits do not follow patterns of Mendelian inheritance.

Epigenetic effect: The term epigenetics is used to describe the study of heritable changes in genome function that occur without a change in DNA sequence. This includes; the study of how patterns of gene expression are passed from one cell to its descendants, how gene expression changes during the differentiation of one cell type into another, and how environmental factors can change the way genes are expressed. DNA methylation is one such change, which can turn off the expression of some genes.

Familial aggregation: Occurrence of a trait in more members of a family than can be readily accounted for by chance. However, disease also can aggregate in families because nongenetic risk factors cluster among relatives. A key measure of clustering or aggregation in families is the recurrence risk, that is, the risk of disease experienced by relatives of a subject with disease.

Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. DNA segment is transcribed into messenger RNA and is finally translated into a protein. Genes comprise the exons that are actually translated (coding regions) and separated by long regions of DNA called introns.

Genetic heterogeneity: The production of the same or similar phenotypes by different genes or different genetic mechanisms in different pedigrees. If different alleles at a locus produce variable expression of a condition is known as allelic heterogeneity and if mutations at different loci produce the same disease phenotype is known as locus heterogeneity.

Genetic polymorphism: A variation in the DNA that is too common to be due merely to new mutation. A polymorphism must have a frequency of at least 1% in the population. The development of DNA markers allowed human gene mapping to start in earnest.

Genome: The genome of an organism is a complete genetic sequence on one set of chromosomes or one of the two sets that a diploid individual carries in every somatic cell. The term genome can also be applied to that stored within organelles that contain their own DNA, as with the mitochondrial genome.

Genome-wide association: A genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits, or the presence or absence of a disease or condition.

Haplotype: A set of closely linked allelic state present on one chromosome which tend to be inherited together. It refers to a collection of specific alleles in a cluster of tightly-linked genes. Haplotypes can be broken down by recombination. The tighter the linkage, the less likely that the haplotype will be broken up by recombination, and will be preserved through subsequent generations.

Linkage analysis: By using the linkage analysis we can trace the pattern of heredity in large, high-risk families, and to locate a disease causing gene mutation by identifying traits that are co-inherited with it. Parametric linkage analysis is usually used to find chromosomal regions linked to a disease that is described with a specific genetic model. This is done by investigating the relations between the disease and genetic markers, that is, well-characterized loci of known position with a clear Mendelian mode of inheritance. When we are studying complex traits such as nonsyndromic cleft lip and or palate we usually do not know the mode of inheritance. In this case we use non-parametric linkage analysis where we do not need to specify the penetrance model or disease allele frequency. Parametric analysis focuses on the co-segregation of the marker and the trait phenotype. Non-parametric analysis focuses on allele-sharing distribution between relatives that share the trait phenotype of interest.

Linkage disequilibrium: Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies. Non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium (LD). Alleles at markers near disease causing genes tend to be in linkage disequilibrium in the affected individuals.

Linkage: Linkage is a physical phenomenon that is due to the physical location of loci on a chromosome. Two loci are said to be linked if sufficiently close to each other on the same chromosome and alleles at these loci co-segregate more often than expected by independent assortment.

LOD score: LOD stands for logarithm of the odds (to the base 10). This is a measure of the likelihood of genetic linkage between loci. For a mendelian character, a lod score greater than +3 is evidence of linkage; one that is less than −2 is evidence against linkage.

Microsatellites: Microsatellites are polymorphic loci present in nuclear and organellar DNA that consist of repeating units of 1-6 base pairs in length. They are typically neutral, co-dominant and are used as molecular markers which have wide-ranging applications in the field of genetics, including kinship and population studies.

Minisatellites: A minisatellite is a section of DNA that consists of a short series of bases 10-60bp.These are also known as variable number tandem repeats (VNTRs). The VNTRs have many alleles and high heterozygosity. The VNTRs are not evenly spread across the genome and are not generally found in coding DNA.

Mutation: A mutation is a permanent change in the DNA sequence of a gene. Mutations in a gene's DNA sequence can alter the amino acid sequence of the protein encoded by the gene. Mutations occur more-or-less randomly throughout the genome and may affect any gene. In a clinical sense, any mutation that disrupts the information contained in DNA and leads to disease. The mechanisms leading to mutations are diverse: from exogen and endogen carcinogens to DNA repair defects. Mutation may be the insertion (addition) or deletion of one or a few nucleotides. An insertion is the integration of an additional fragment into the DNA, deletion is the elimination of a DNA fragment. Inversion is the reversal of a DNA fragment by excision and re-integration in the opposite direction. Substitution is the replacement of a base (A,T,C, or G) with another. A mutation can be a change in single base pairs or can involve a longer DNA fragment. The length of the changed DNA does not necessarily correspond with the impact of the mutation: in some cases, the exchange of a single base pair can have devastating consequences while, in other cases, a change in a long DNA segment may have no recognisable effect at all.

Penetrance: Penetrance is a term used in genetics describing the proportion of individuals carrying a particular variation of a gene (allele or genotype) that also expresses a particular phenotype. A penetrance of 100% means that the associated phenotype always occurs when the corresponding genotype is present. Similarly, if only 50% of those carrying a particular allele exhibit a phenotype, the penetrance is 50%.

Recombination: Recombination is an event, occurring by the crossing-over of chromosomes during meiosis, in which DNA is exchanged between a pair of chromosomes. Thus two genes that were previously unlinked, being on separate chromosomes, can become linked because of recombination; and vice versa: linked genes may become unlinked. This process leads to offspring having different combinations of genes from their parents and can produce new chimeric alleles.

Restriction fragment length polymorphisms (RFLPs): The first generation of DNA markers was RFLPs. RFLPs are based on the analysis of patters derived from a DNA sequence cleaved by using known restriction enzymes. Differences are noticed when the length of fragments are not the same, telling us that the restriction enzyme cut the DNA at two unrelated locations. RFLPs have only two alleles: the site is present or it is absent.

Single nucleotide polymorphisms (SNPs): SNP is a DNA sequence variation occurring when a single nucleotide - A, T, C, or G - in the genome differs between members of a species or between paired chromosomes of an individual. Single nucleotide polymorphisms may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions between genes. SNPs within a coding sequence will not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code.

Whole genome scan: Linkage analysis in which markers placed at regular intervals and covering the whole genome are typed. It is often the first approach when no genetic information is available about a particular phenotype.

 ╗ References Top

1.Schutte BC, Murray JC. The many faces and factors of orofacial clefts. Hum Mol Genet 1999;8:1853-9.  Back to cited text no. 1    
2.Murray JC. Face facts: Genes, environment, and clefts. Am J Hum Genet 1995;57:227-32.  Back to cited text no. 2    
3.Gaspar DA, Matioli SR, de Cαssia Pavanello R, Ara˙jo BC, Alonso N, Wyszynski D, et al . 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. Eur J Hum Genet 2004;12:521-6.  Back to cited text no. 3    
4.Lammer EJ, Shaw GM, Iovannisci DM, Finnell RH. Maternal smoking, genetic variation of glutathione s-transferases, and risk for orofacial clefts. Epidemiology 2005;16:698-701.  Back to cited text no. 4    
5.Shaw GM, Iovannisci DM, Yang W, Finnell RH, Carmichael SL, Cheng S, et al . Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts. Am J Epidemiol 2005;162:1207-14.  Back to cited text no. 5    
6.Mitchell LE, Murray JC, O'Brien S, Christensen K. Retinoic acid receptor alpha gene variants, multivitamin use, and liver intake as risk factors for oral clefts: A population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 2003;158:69-76.  Back to cited text no. 6    
7.Lammer EJ, Shaw GM, Iovannisci DM, Finnell RH. Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl-N-transferase 1 (NAT1), and risk for orofacial clefts. Birth Defects Res A Clin Mol Teratol 2004;70:846-52.  Back to cited text no. 7    
8.Marazita ML, Field LL, Cooper ME, Tobias R, Maher BS, Peanchitlertkajorn S, et al . Genome scan for loci involved in cleft lip with or without cleft palate, in Chinese multiplex families. Am J Hum Genet 2002;71:349-64.  Back to cited text no. 8    
9.Radhakrishna U, Ratnamala U, Gaines M, Beiraghi S, Hutchings D, Golla J, et al . Genomewide scan for nonsyndromic cleft lip and palate in multigenerational Indian families reveals significant evidence of linkage at 13q33.1-34. Am J Hum Genet 2006;79:580-5.  Back to cited text no. 9    
10.Beiraghi S, Nath SK, Gaines M, Mandhyan DD, Hutchings D, Ratnamala U, et al . Autosomal dominant nonsyndromic cleft lip and palate: Significant evidence of linkage at 18q21.1. Am J Hum Genet 2007;81:180-8.  Back to cited text no. 10    
11.Moore GE, Ivens A, Chambers J, Farrall M, Williamson R, Page DC, et al . Linkage of an X-chromosome cleft palate gene. Nature 1987;326:91-2.  Back to cited text no. 11    
12.Forbes SA, Brennan L, Richardson M, Coffey A, Cole CG, Gregory SG, et al . Refined mapping and YAC contig construction of the X-linked cleft palate and ankyloglossia locus (CPX) including the proximal X-Y homology breakpoint within Xq21.3. Genomics 1996;31:36-43.  Back to cited text no. 12    
13.Brewer CM, Leek JP, Green AJ, Holloway S, Bonthron DT, Markham AF, et al . A locus for isolated cleft palate, located on human chromosome 2q32. Am J Hum Genet 1999;65:387-96..  Back to cited text no. 13    
14.Carreno H, Paredes M, Tιllez G, Palomino H, Blanco R. Association of non-syndromic cleft lip and cleft palate with microsatellite markers located in 6p. Rev Med Chil 1999;127:1189-98.  Back to cited text no. 14    
15.Prescott NJ, Lees MM, Winter RM, Malcolm S. Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib-pairs. Hum Genet 2000;106:345-50.  Back to cited text no. 15    
16.Schultz RE, Cooper ME, Daack-Hirsch S, Shi M, Nepomucena B, Graf KA, et al . Targeted scan of fifteen regions for nonsyndromic cleft lip and palate in Filipino families. Am J Med Genet Am 2004;125:17-22.  Back to cited text no. 16    
17.Ardinger HH, Buetow KH, Bell GI, Bardach J, VanDemark DR, Murray JC. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet 1989;45:348-53.  Back to cited text no. 17    
18.Wyszynski DF, Maestri N, Lewanda AF, McIntosh I, Smith EA, Garcνa-Delgado C, et al . No evidence of linkage for cleft lip with or without cleft palate to a marker near the transforming growth factor alpha locus in two populations. Hum Hered 1997;47:101-9.  Back to cited text no. 18    
19.Warrington A, Vieira AR, Christensen K, Orioli IM, Castilla EE, Romitti PA, et al . Genetic evidence for the role of loci at 19q13 in cleft lip and palate. J Med Genet 2006;43:e26.  Back to cited text no. 19    
20.Beiraghi S, Zhou M, Talmadge CB, Went-Sumegi N, Davis JR, Huang D, et al . Identification and characterization of a novel gene disrupted by a pericentric inversion inv(4)(p13.1q21.1) in a family with cleft lip. Gene 2003;309:11-21.  Back to cited text no. 20    
21.Lidral AC, Murray JC, Buetow KH, Basart AM, Schearer H, Shiang R, et al . Studies of the candidate genes TGFB2, MSX1, TGFA, and TGFB3 in the etiology of cleft lip and palate in the Philippines. Cleft Palate Craniofac J 1997;34:1-6.  Back to cited text no. 21    
22.Vieira AR, Avila JR, Daack-Hirsch S, Dragan E, Fιlix TM, Rahimov F, et al . Medical sequencing of candidate genes for nonsyndromic cleft lip and palate. PLoS Genet 2005;1:e64.  Back to cited text no. 22    
23.Tongkobpetch S, Siriwan P, Shotelersuk V. MSX1 mutations contribute to nonsyndromic cleft lip in a Thai population. J Hum Genet 2006;51:671-6.  Back to cited text no. 23    
24.Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, et al . Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med 2004;351:769-80.  Back to cited text no. 24    
25.Blanton SH, Cortez A, Stal S, Mulliken JB, Finnell RH, Hecht JT. Variation in IRF6 contributes to nonsyndromic cleft lip and palate. Am J Med Genet Am 2005;137:259-62.  Back to cited text no. 25    
26.Suzuki K, Hu D, Bustos T, Zlotogora J, Richieri-Costa A, Helms JA, et al . Mutations of PVRL1, encoding a cell-cell adhesion molecule/ herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat Genet 2000;25:427-30.  Back to cited text no. 26    
27.Scapoli L, Palmieri A, Martinelli M, Vaccari C, Marchesini J, Pezzetti F, et al . Study of the PVRL1 gene in Italian nonsyndromic cleft lip patients with or without cleft palate. Ann Hum Genet 2006;70:410-3.  Back to cited text no. 27    
28.Brunner HG, Hamel BC, Bokhoven Hv H. P63 gene mutations and human developmental syndromes. Am J Med Genet 2002;112:284-90.  Back to cited text no. 28    
29.Leoyklang P, Siriwan P, Shotelersuk V. A mutation of the p63 gene in non-syndromic cleft lip. J Med Genet 2006;43:e28.  Back to cited text no. 29    
30.Alkuraya FS, Saadi I, Lund JJ, Turbe-Doan A, Morton CC, Maas RL. SUMO1 haploinsufficiency leads to cleft lip and palate. Science 2006;313:1751.  Back to cited text no. 30    
31.Berge SJ, Plath H, Van de Vondel PT, Appel T, Niederhagen B, Von Lindern JJ, et al . Fetal cleft lip and palate: Sonographic diagnosis, chromosomal abnormalities, associated anomalies and postnatal outcome in 70 fetuses. Ultrasound Obstet Gynecol 2001;18:422-31.  Back to cited text no. 31    
32.Jezewski PA, Vieira AR, Nishimura C, Ludwig B, Johnson M, O'Brien SE, et al . Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet 2003;40:399-407.  Back to cited text no. 32    
33.Wyszynski DF, Wu T. Prenatal and perinatal factors associated with isolated oral clefting. Cleft Palate Craniofac J 2002;39:370-5.  Back to cited text no. 33    
34.Scapoli L, Martinelli M, Pezzetti F, Carinci F, Bodo M, Tognon M, et al . Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate. Hum Genet 2002;110:15-20.  Back to cited text no. 34    
35.Martinelli M, Scapoli L, Pezzetti F, Carinci F, Francioso F, Baciliero U, et al . Linkage analysis of three candidate regions of chromosome 1 in nonsyndromic familial orofacial cleft. Ann Hum Genet 2001;65:465-71.  Back to cited text no. 35    
36.Carinci F, Pezzetti F, Scapoli L, Martinelli M, Carinci P, Tognon M. Genetics of nonsyndromic cleft lip and palate: A review of international studies and data regarding the Italian population. Cleft Palate Craniofac J 2000;37:33-40.  Back to cited text no. 36    
37.Beiraghi S, Foroud T, Diouhy S, Bixler D, Conneally PM, Delozier-Blanchet D, Hodes ME. Possible localization of a major gene for cleft lip and palate to 4q. Clin Genet 1994;46:255-6.  Back to cited text no. 37    
38.Mitchell LE, Healey SC, Chenevix-Trench G. Evidence for an association between nonsyndromic cleft lip with or without cleft palate and a gene located on the long arm of chromosome 4. Am J Hum Genet 1995;57:1130-6.  Back to cited text no. 38    
39.Blanton SH, Crowder E, Malcolm S, Winter R, Gasser DL, Stal S, et al . Exclusion of linkage between cleft lip with or without cleft palate and markers on chromosomes 4 and 6. Am J Hum Genet 1996;58:239-41.  Back to cited text no. 39    
40.Pezzetti F, Scapoli L, Martinelli M, Carinci F, Bodo M, Carinci P, et al . A locus in 2p13-p14 (OFC2), in addition to that mapped in 6p23, is involved in nonsyndromic familial orofacial cleft malformation. Genomics 1998;50:299-305.  Back to cited text no. 40    
41.Wong FK, Hagberg C, Karsten A, Larson O, Gustavsson M, Huggare J, et al . Linkage analysis of candidate regions in Swedish nonsyndromic cleft lip with or without cleft palate families. Cleft Palate Craniofac J 2000;37:357-62.  Back to cited text no. 41    
42.Stein J, Mulliken JB, Stal S, Gasser DL, Malcolm S, Winter R, et al . Nonsyndromic cleft lip with or without cleft palate: Evidence of linkage to BCL3 in 17 multigenerational families. Am J Hum Genet 1995;57:257-72.  Back to cited text no. 42    
43.Martinelli M, Scapoli L, Pezzetti F, Carinci F, Carinci P, Baciliero U, et al . M. Suggestive linkage between markers on chromosome 19q13.2 and nonsyndromic orofacial cleft malformation. Genomics 1998;51:177-81.  Back to cited text no. 43    
44.Wyszynski DF, Albacha-Hejazi H, Aldirani M, Hammod M, Shkair H, Karam A, et al . A genome-wide scan for loci predisposing to non-syndromic cleft lip with or without cleft palate in two large Syrian families. Am J Med Genet Am 2003;123:140-7.  Back to cited text no. 44    
45.Zeiger JS, Hetmanski JB, Beaty TH, VanderKolk CA, Wyszynski DF, Bailey-Wilson JE, et al . Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2. Eur J Hum Genet 2003;11:835-9.  Back to cited text no. 45    
46.Field LL, Ray AK, Cooper ME, Goldstein T, Shaw DF, Marazita ML. Genome scan for loci involved in nonsyndromic cleft lip with or without cleft palate in families from West Bengal, India. Am J Med Genet A 2004;130:265-71.  Back to cited text no. 46    
47.Marazita ML, Field LL, Tunηbilek G, Cooper ME, Goldstein T, GŘrsu KG. Genome-scan for loci involved in cleft lip with or without cleft palate in consanguineous families from Turkey. Am J Med Genet Am 2004;126:111-22.  Back to cited text no. 47    
48.Marazita ML, Murray JC, Lidral AC, Arcos-Burgos M, Cooper ME, Goldstein T, et al . Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32- 35. Am J Hum Genet 2004;75:161-73.  Back to cited text no. 48    
49.Lander E, Kruglyak L. Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nat Genet 1995;11:241-7.  Back to cited text no. 49    
50.Osoegawa K, Vessere GM, Utami KH, Mansilla MA, Johnson MK, Riley BM, et al . Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridisation. J Med Genet 2008;45:81-6.  Back to cited text no. 50    
51.Zhang WG, Luo SJ, Zhu SF, Tang SM. Comparative genomic hybridization analysis of nonsyndromic cleft lip with palate. Zhonghua Zheng Xing Wai Ke Za Zhi 2008;24:123-5.  Back to cited text no. 51    
52.Holder SE, Vintiner GM, Farren B, Malcolm S, Winter RM. Confirmation of an association between RFLPs at the transforming growth factor-alpha locus and non-syndromic cleft lip and palate. J Med Genet 1992;29:390-2.  Back to cited text no. 52    
53.Sassani R, Bartlett SP, Feng H, Goldner-Sauve A, Haq AK, Buetow KH, et al . Association between alleles of the transforming growth factor-alpha locus and the occurrence of cleft lip. Am J Med Genet 1993;45:565-9.  Back to cited text no. 53    
54.Mitchell LE. Genetic epidemiology of birth defects: Nonsyndromic cleft lip and neural tube defects. Epidemiol Rev 1997;19:61-8.  Back to cited text no. 54    
55.Romitti PA, Lidral AC, Munger RG, Daack-Hirsch S, Burns TL, Murray JC. Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: Evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts. Teratology 1999;59:39-50.  Back to cited text no. 55    
56.Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet 2003;361:598-604.  Back to cited text no. 56    
57.Birnbaum S, Ludwig KU, Reutter H, Herms S, Steffens M, Rubini M, et al . Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet 2009;41:473-7.  Back to cited text no. 57    
58.Stanier P, Moore GE. Genetics of cleft lip and palate: Syndromic genes contribute to the incidence of non-syndromic clefts. Hum Mol Genet 2004;13:R73-81.  Back to cited text no. 58    
59.Van der Woude A. Fistula labii inferioris congenita and its association with cleft lip and palate. Am J Hum Genet 1954;6:244-56.  Back to cited text no. 59    
60.Schutte BC, Bjork BC, Coppage KB, Malik MI, Gregory SG, Scott DJ, et al . A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32- q41. Genome Res 2000;10:81-94.  Back to cited text no. 60    
61.Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, et al . Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 2002;32:285-9.  Back to cited text no. 61    
62.Scapoli L, Palmieri A, Pezzetti F, Carinci F, Marchesini J, Martinelli M, et al . Investigation of the W185X nonsense mutation of PVRL1 gene in Italian nonsyndromic cleft lip and palate patients. Am J Med Genet Am 2004;127:211.  Back to cited text no. 62    
63.Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, et al . Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nat Genet 2008;40:1341-7.  Back to cited text no. 63    
64.Morishita M, Shiba R, Chiyo H, Furuyama J, Fujita H, Atsumi Y. The oral manifestations of 4p- syndrome. J Oral Maxillofac Surg 1983;41:601-5.  Back to cited text no. 64    
65.Nieminen P, Kotilainen J, Aalto Y, Knuutila S, Pirinen S, Thesleff I. MSX1 gene is deleted in Wolf-Hirschhorn syndrome patients with oligodontia. J Dent Res 2003;82:1013-7.  Back to cited text no. 65    
66.van den Boogaard MJ, Dorland M, Beemer FA, van Amstel HK. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 2000;24:342-3.  Back to cited text no. 66    
67.Dode C, Levilliers J, Dupont JM, De Paepe A, Le Dű N, Soussi-Yanicostas N, et al . Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003;33:463-5.  Back to cited text no. 67    
68.Dode C, Hardelin JP. Kallmann syndrome: Fibroblast growth factor signaling insufficiency? J Mol Med 2004;82:725-34.  Back to cited text no. 68    
69.Dodι C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, et al . Kallmann syndrome: Mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet 2006;2:e175.  Back to cited text no. 69    
70.Riley BM, Murray JC. Sequence evaluation of FGF and FGFR gene conserved non-coding elements in non-syndromic cleft lip and palate cases. Am J Med Genet Am 2007;143:3228-34.  Back to cited text no. 70    
71.Sozen MA, Suzuki K, Tolarova MM, Bustos T, Fernαndez Iglesias JE, Spritz RA. Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela. Nat Genet 2001;29:141-2.  Back to cited text no. 71    
72.Scapoli L, Marchesini J, Martinelli M, Pezzetti F, Carinci F, Palmieri A, et al . Study of folate receptor genes in nonsyndromic familial and sporadic cleft lip with or without cleft palate cases. Am J Med Genet Am 2005;132:302-4.  Back to cited text no. 72    
73.Avila JR, Jezewski PA, Vieira AR, Orioli IM, Castilla EE, Christensen K, et al . PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations. Am J Med Genet A 2006;140:2562-70.  Back to cited text no. 73    
74.van Bokhoven H, Brunner HG. Splitting p63. Am J Hum Genet 2002;71:1-13.  Back to cited text no. 74    
75.Braybrook C, Lisgo S, Doudney K, Henderson D, Marηano AC, Strachan T, et al . Craniofacial expression of human and murine TBX22 correlates with the cleft palate and ankyloglossia phenotype observed in CPX patients. Hum Mol Genet 2002;11:2793-804.  Back to cited text no. 75    
76.Marcano AC, Doudney K, Braybrook C, Squires R, Patton MA, Lees MM, et al . TBX22 mutations are a frequent cause of cleft palate. J Med Genet 2004;41:68-74.  Back to cited text no. 76    
77.Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, et al . Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 2000;67:1382-8.  Back to cited text no. 77    
78.Bahuau M, Houdayer C, Tredano M, Soupre V, Couderc R, Vazquez MP. FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate. Clin Genet 2002;62:470-3.  Back to cited text no. 78    
79.Castanet M, Park SM, Smith A, Bost M, Lιger J, Lyonnet S, et al . A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. Hum Mol Genet 2002;11:2051-9.  Back to cited text no. 79    
80.Thyagarajan T, Totey S, Danton MJ, Kulkarni AB. Genetically altered mouse models: The good, the bad, and the ugly. Crit Rev Oral Biol Med 2003;14:154-74.  Back to cited text no. 80    
81.Herron BJ, Lu W, Rao C, Liu S, Peters H, Bronson RT, et al . Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis. Nat Genet 2002;30:185-9.  Back to cited text no. 81    
82.Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, et al . Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 1994;368:703-10.  Back to cited text no. 82    
83.Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, et al . Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 1998;125:825-36.  Back to cited text no. 83    
84.Kimmel CB, Ullmann B, Walker M, Miller CT, Crump JG. Endothelin 1-mediated regulation of pharyngeal bone development in zebrafish. Development 2003;130:1339-51.  Back to cited text no. 84    
85.Pezzetti F, Scapoli L, Martinelli M, Carinci F, Brunelli G, Carls FP, et al . Linkage analysis of candidate endothelin pathway genes in nonsyndromic familial orofacial cleft. Ann Hum Genet 2000;64:341-7.  Back to cited text no. 85    
86.Condie BG, Bain G, Gottlieb DI, Capecchi MR. Cleft palate in mice with a targeted mutation in the gamma-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67. Proc Natl Acad Sci USA 1997;94:11451-5.  Back to cited text no. 86    
87.Ding R, Tsunekawa N, Obata K. Cleft palate by picrotoxin or 3-MP and palatal shelf elevation in GABA-deficient mice. Neurotoxicol Teratol 2004;26:587-92.  Back to cited text no. 87    
88.Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN, et al . Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet 1995;11:409-14.  Back to cited text no. 88    
89.Lu MF, Cheng HT, Lacy AR, Kern MJ, Argao EA, Potter SS, et al . Paired-related homeobox genes cooperate in handplate and hindlimb zeugopod morphogenesis. Dev Biol 1999;205:145-57.  Back to cited text no. 89    
90.Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development 2002;129:4135-46.  Back to cited text no. 90    
91.Warkany J, Nelson RS. Appearance of skeletal abonormalities in the offspring of rats reared on a deficient diet. Science 1940;92:383-4.  Back to cited text no. 91    
92.Lieff S, Olshan AF, Werler M, Strauss RP, Smith J, Mitchell A. Maternal cigarette smoking during pregnancy and risk of oral clefts in newborns. Am J Epidemiol 1999;150:683-94.  Back to cited text no. 92    
93.Shaw GM, Lammer EJ. Maternal periconceptional alcohol consumption and risk for orofacial clefts. J Pediatr 1999;134:298-303.  Back to cited text no. 93    
94.Fraser FC, Warburton D. No association of emotional stress or vitamin supplement during pregnancy to cleft lip or palate in man. Plast Reconstr Surg 1964;33:395-9.  Back to cited text no. 94    
95.Walker BE. Induction of cleft palate in rabbits by several glucocorticoids. Proc Soc Exp Biol Med 1967;125:1281-4.  Back to cited text no. 95    
96.Walker BE. Induction of cleft palate in rats with antiinflammatory drugs. Teratology 1971;4:39-42.  Back to cited text no. 96    
97.Marazita ML, Jaskoll T, Melnick M. Corticosteroid-induced cleft palate in short-ear mice. J Craniofac Genet Dev Biol 1988;8:47-51.  Back to cited text no. 97    
98.Fawcett LB, Buck SJ, Beckman DA, Brent RL. Is there a no-effect dose for corticosteroid-induced cleft palate? The contribution of endogenous corticosterone to the incidence of cleft palate in mice. Pediatr Res 1996;39:856-61.  Back to cited text no. 98    
99.Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:242-4.  Back to cited text no. 99    
100.Rodrνguez-Pinilla E, Martνnez-Frνas ML. Corticosteroids during pregnancy and oral clefts: A case-control study. Teratology 1998;58:2-5.  Back to cited text no. 100    
101.Ericson A, Kδllιn B, Westerholm P. Cigarette smoking as an etiologic factor in cleft lip and palate. Am J Obstet Gynecol 1979;135:348-51.  Back to cited text no. 101    
102.Khoury MJ, Weinstein A, Panny S, Holtzman NA, Lindsay PK, Farrel K, et al . Maternal cigarette smoking and oral clefts: A population-based study. Am J Public Health 1987;77:623-5.  Back to cited text no. 102    
103.Chung KC, Kowalski CP, Kim HM, Buchman SR. Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate. Plast Reconstr Surg 2000;105:485-91.  Back to cited text no. 103    
104.Malloy MH, Kleinman JC, Bakewell JM, Schramm WF, Land GH. Maternal smoking during pregnancy: No association with congenital malformations in Missouri 1980-83. Am J Public Health 1989;79:1234-6.  Back to cited text no. 104    
105.Wyszynski DF, Duffy DL, Beaty TH. Maternal cigarette smoking and oral clefts: A meta-analysis. Cleft Palate Craniofac J 1997;34:206- 10.  Back to cited text no. 105    
106.van Rooij IA, Wegerif MJ, Roelofs HM, Peters WH, Kuijpers-Jagtman AM, Zielhuis GA, et al . Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: A gene-environment interaction. Epidemiology 2001;12:502-7.  Back to cited text no. 106    
107.Beaty TH, Hetmanski JB, Zeiger JS, Fan YT, Liang KY, VanderKolk CA, et al . Testing candidate genes for non-syndromic oral clefts using a case-parent trio design. Genet Epidemiol 2002;22:1-11.  Back to cited text no. 107    
108.Jones KL, Smith DW, Ulleland CN, Streissguth P. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973;1:1267-71.  Back to cited text no. 108    
109.Abel EL. Fetal alcohol syndrome: The American paradox. Alcohol Alcohol 1998;33:195-201.  Back to cited text no. 109    
110.Munger RG, Romitti PA, Daack-Hirsch S, Burns TL, Murray JC, Hanson J. Maternal alcohol use and risk of orofacial cleft birth defects. Teratology 1996;54:27-33.  Back to cited text no. 110    
111.Natsume N, Kawai T, Ogi N, Yoshida W. Maternal risk factors in cleft lip and palate: Case control study. Br J Oral Maxillofac Surg 2000;38:23-5.  Back to cited text no. 111    
112.DeRoo LA, Wilcox AJ, Drevon CA, Lie RT. First-trimester maternal alcohol consumption and the risk of infant oral clefts in Norway: A population-based case-control study. Am J Epidemiol 2008;168:638-46.  Back to cited text no. 112    
113.Chevrier C, Perret C, Bahuau M, Nelva A, Herman C, Francannet C, et al . Interaction between the ADH1C polymorphism and maternal alcohol intake in the risk of nonsyndromic oral clefts: An evaluation of the contribution of child and maternal genotypes. Birth Defects Res A Clin Mol Teratol 2005;73:114-22.  Back to cited text no. 113    
114.Chevrier C, Perret C, Bahuau M, Nelva A, Herman C, Francannet C, et al . Fetal and maternal CYP2E1 genotypes and the risk of nonsyndromic oral clefts. Am J Med Genet Am 2007;143:1382-5.  Back to cited text no. 114    
115.Burgoon JM, Selhub J, Nadeau M, Sadler TW. Investigation of the effects of folate deficiency on embryonic development through the establishment of a folate deficient mouse model. Teratology 2002;65:219-27.  Back to cited text no. 115    
116.van Rooij IA, Vermeij-Keers C, Kluijtmans LA, Ocke MC, Zielhuis GA, Goorhuis-Brouwer SM, et al . Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate? Am J Epidemiol 2003;157:583-91.  Back to cited text no. 116    
117.Little J, Gilmour M, Mossey PA, Fitzpatrick D, Cardy A, Clayton- Smith J, et al . Folate and clefts of the lip and palate--a U.K.-based case-control study: Part II: Biochemical and genetic analysis. Cleft Palate Craniofac J 2008;45:428-38.  Back to cited text no. 117    
118.Rozen R. Genetic predisposition to hyperhomocysteinemia: Deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost 1997;78:523-6.  Back to cited text no. 118    
119.Mostowska A, Hozyasz KK, Jagodzinski PP. Maternal MTR genotype contributes to the risk of non-syndromic cleft lip and palate in the Polish population. Clin Genet 2006;69:512-7.  Back to cited text no. 119    
120.Chevrier C, Perret C, Bahuau M, Zhu H, Nelva A, Herman C, et al . Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts. Am J Med Genet Am 2007;143:248-57.  Back to cited text no. 120    
121.Pezzetti F, Martinelli M, Scapoli L, Carinci F, Palmieri A, Marchesini J, et al . Maternal MTHFR variant forms increase the risk in offspring of isolated nonsyndromic cleft lip with or without cleft palate. Hum Mutat 2004;24:104-5.  Back to cited text no. 121    
122.Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey DR, Abyholm F, et al . Folic acid supplements and risk of facial clefts: National population based case-control study. BMJ 2007;334:464.  Back to cited text no. 122    
123.Suzuki Y, Jezewski PA, Machida J, Watanabe Y, Shi M, Cooper ME, et al . In a Vietnamese population, MSX1 variants contribute to cleft lip and palate. Genet Med 2004;6:117-25.  Back to cited text no. 123    
124.Park J, Park BY, Kim HS, Lee JE, Suh I, Nam CM, et al . MSX1 polymorphism associated with risk of oral cleft in Korea: Evidence from case-parent trio and case-control studies. Yonsei Med J 2007;48:101-8.  Back to cited text no. 124    
125.Ichikawa E, Watanabe A, Nakano Y, Akita S, Hirano A, Kinoshita A, et al . 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. J Hum Genet 2006;51:38-46.  Back to cited text no. 125    
126.Lidral AC, Romitti PA, Basart AM, Doetschman T, Leysens NJ, Daack-Hirsch S, et al . Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. Am J Hum Genet 1998;63:557-68.  Back to cited text no. 126    
127.Leoyklang P, Suphapeetiporn K, Siriwan P, Desudchit T, Chaowanapanja P, Gahl WA, et al . Heterozygous nonsense mutation SATB2 associated with cleft palate, osteoporosis, and cognitive defects. Hum Mutat 2007;28:732-8.  Back to cited text no. 127    
128.Watanabe A, Akita S, Tin NT, Natsume N, Nakano Y, Niikawa N, et al . A mutation in RYK is a genetic factor for nonsyndromic cleft lip and palate. Cleft Palate Craniofac J 2006;43:310-6.  Back to cited text no. 128    
129.Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, et al . TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet 2008;82:1171-7.  Back to cited text no. 129    
130.Stoll C, Qian JF, Feingold J, Sauvage P, May E. Genetic variation in transforming growth factor alpha: Possible association of BamHI polymorphism with bilateral sporadic cleft lip and palate. Hum Genet 1993;92:81-2.  Back to cited text no. 130    
131.Jara L, Blanco R, Chiffelle I, Palomino H, Carreρo H. Association between alleles of the transforming growth factor alpha locus and cleft lip and palate in the Chilean population. Am J Med Genet 1995;57:548-51.  Back to cited text no. 131    
132.Tanabe A, Taketani S, Endo-Ichikawa Y, Tokunaga R, Ogawa Y, Hiramoto M. Analysis of the candidate genes responsible for non-syndromic cleft lip and palate in Japanese people. Clin Sci (Lond) 2000;99:105-11.  Back to cited text no. 132    
133.Stoll C, Mengsteab S, Stoll D, Riediger D, Gressner AM, Weiskirchen R. Analysis of polymorphic TGFB1 codons 10, 25, and 263 in a German patient group with non-syndromic cleft lip, alveolus, and palate compared with healthy adults. BMC Med Genet 2004;5:15.  Back to cited text no. 133    
134.Mitchell LE, Murray JC, O'Brien S, Christensen K. Evaluation of two putative susceptibility loci for oral clefts in the Danish population. Am J Epidemiol 2001;153:1007-15.  Back to cited text no. 134    
135.Lu W, Volcik K, Zhu H, Wen S, Shaw GM, Lammer EJ, et al . Genetic variation in the proto-oncogene SKI and risk for orofacial clefting. Mol Genet Metab 2005;86:412-6.  Back to cited text no. 135    
136.Albuisson J, Pκcheux C, Carel JC, Lacombe D, Leheup B, Lapuzina P, et al . Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum Mutat 2005;25:98-9.  Back to cited text no. 136    
137.Ray AK, Marazita ML, Pathak R, Beever CL, Cooper ME, Goldstein T, et al . TP63 mutation and clefting modifier genes in an EEC syndrome family. Clin Genet 2004;66:217-22.  Back to cited text no. 137    
138.Tongkobpetch S, Suphapeetiporn K, Siriwan P, Shotelersuk V. Study of the poliovirus receptor related-1 gene in Thai patients with non-syndromic cleft lip with or without cleft palate. Int J Oral Maxillofac Surg 2008;37:550-3.  Back to cited text no. 138    
139.Mansilla MA, Cooper ME, Goldstein T, Castilla EE, Lopez Camelo JS, Marazita ML, et al . Contributions of PTCH gene variants to isolated cleft lip and palate. Cleft Palate Craniofac J 2006;43:21-9.  Back to cited text no. 139    
140.Barrow LL, Wines ME, Romitti PA, Holdener BC, Murray JC. Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2): Structure, gene mapping, polymorphisms, and candidate evaluation for human orofacial clefts. Teratology 2002;66:85-90.  Back to cited text no. 140    
141.Martinelli M, Scapoli L, Pezzetti F, Carinci F, Carinci P, Stabellini G, et al . C677T variant form at the MTHFR gene and CL/P: A risk factor for mothers? Am J Med Genet 2001;98:357-60.  Back to cited text no. 141    
142.Wan WD, Wang LJ, Zhou XP, Zhou DL, Zhang QG, Huang JL, et al . Relationship between nonsyndromic cleft lip with or without cleft palate (NSCL/P) and genetic polymorphisms of MTHFR C677T and A1298C. Zhonghua Zheng Xing Wai Ke Za Zhi 2006;22:8-11.  Back to cited text no. 142    
143.Brandalize AP, Bandinelli E, Borba JB, Fιlix TM, Roisenberg I, SchŘler-Faccini L. Polymorphisms in genes MTHFR, MTR and MTRR are not risk factors for cleft lip/palate in South Brazil. Braz J Med Biol Res 2007;40:787-91.  Back to cited text no. 143    
144.Palmieri A, Masiero E, Martinelli M, Scapoli L, Pezzetti F, Caramelli E, et al . The MTHFD1 gene is not involved in cleft lip with or without palate onset among the Italian population. Ann Hum Genet 2008;72:297-9.  Back to cited text no. 144    
145.Martinelli M, Scapoli L, Palmieri A, Pezzetti F, Baciliero U, Padula E, et al . Study of four genes belonging to the folate pathway: Transcobalamin 2 is involved in the onset of non-syndromic cleft lip with or without cleft palate. Hum Mutat 2006;27:294.  Back to cited text no. 145    
146.Vieira AR, Murray JC, Trembath D, Orioli IM, Castilla EE, Cooper ME, et al . Studies of reduced folate carrier 1 (RFC1) A80G and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with neural tube and orofacial cleft defects. Am J Med Genet Am 2005;135:220-3.  Back to cited text no. 146    
147.Bianchi F, Calzolari E, Ciulli L, Cordier S, Gualandi F, Pierini A, et al . Environment and genetics in the etiology of cleft lip and cleft palate with reference to the role of folic acid. Epidemiol Prev 2000;24:21-7.  Back to cited text no. 147    
148.Zhu WC, Xu LX, Li SF, Li JY. Dental caries in children with cleft lip and/or palate in China. Sichuan Da Xue Xue Bao Yi Xue Ban 2007;38:697-700.  Back to cited text no. 148    
149.Zhu H, Curry S, Wen S, Wicker NJ, Shaw GM, Lammer EJ, et al . Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts? Am J Med Genet Am 2005;135:274-7.  Back to cited text no. 149    
150.Kayano S, Suzuki Y, Kanno K, Aoki Y, Kure S, Yamada A, et al . Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT). Am J Med Genet Am 2004;130:40-4.  Back to cited text no. 150    
151.Shi M, Christensen K, Weinberg CR, Romitti P, Bathum L, Lozada A, et al . Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants. Am J Hum Genet 2007;80:76-90.  Back to cited text no. 151    
152.Grunert RR, Braune A, Schnackenberg E, Schloot W, Krause HR. Genetic differences in enzymes of folic acid metabolism in patients with lip-jaw-palate clefts and their relatives. Mund Kiefer Gesichtschir 2002;6:131-3.  Back to cited text no. 152    
153.Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH, Shaw GM. Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J 2007;44:366-73.  Back to cited text no. 153    
154.Chenevix-Trench G, Jones K, Green AC, Duffy DL, Martin NG. Cleft lip with or without cleft palate: Associations with transforming growth factor alpha and retinoic acid receptor loci. Am J Hum Genet 1992;51:1377-85.  Back to cited text no. 154    
155.Vintiner GM, Lo KK, Holder SE, Winter RM, Malcolm S. Exclusion of candidate genes from a role in cleft lip with or without cleft palate: Linkage and association studies. J Med Genet 1993;30:773-8.  Back to cited text no. 155    
156.Peanchitlertkajorn S, Cooper ME, Liu YE, Field LL, Marazita ML. Chromosome 17: Gene mapping studies of cleft lip with or without cleft palate in Chinese families. Cleft Palate Craniofac J 2003;40:71-9.  Back to cited text no. 156    


  [Table 1]

This article has been cited by
1 CBS c.844ins68 Polymorphism Frequencies in Control Populations: Implications on Nonsyndromic Cleft Lip With or Without Cleft Palate
Jyotsna Murthy,Saikrishna Lakkakula,Venkatesh Babu Gurramkonda,Ram Mohan Pathapati,Rajasekhar Maram,Bhaskar V.K.S. Lakkakula
The Cleft Palate-Craniofacial Journal. 2015; 52(1): 49
[Pubmed] | [DOI]
2 Sequencing of the interferon regulatory factor 6 (IRF6) gene and correlation to its phenotypes in familial non-syndromic cleft lip and palate in North Indian population
Rohit Khanna,Tripti Tikku,Gulshan Subodh Jain,Kamna Srivastava,Mahendra P Darokar,Raj Kumar Mishra
European Journal of Plastic Surgery. 2014;
[Pubmed] | [DOI]
3 Developmental profiles of the murine palatal methylome
Ratnam S. Seelan,Savitri N. Appana,Partha Mukhopadhyay,Dennis R. Warner,Guy N. Brock,M. Michele Pisano,Robert M. Greene
Birth Defects Research Part A: Clinical and Molecular Teratology. 2013; 97(4): 171
[Pubmed] | [DOI]
4 Developmental profiles of the murine palatal methylome
Seelan, R.S. and Appana, S.N. and Mukhopadhyay, P. and Warner, D.R. and Brock, G.N. and Pisano, M.M. and Greene, R.M.
Birth Defects Research Part A - Clinical and Molecular Teratology. 2013; 97(4): 171-186
5 No evidence of association between 8q24 and susceptibility to nonsyndromic cleft lip with or without palate in Japanese population
Hikida, M. and Tsuda, M. and Watanabe, A. and Kinoshita, A. and Akita, S. and Hirano, A. and Uchiyama, T. and Yoshiura, K.-I.
Cleft Palate-Craniofacial Journal. 2012; 49(6): 714-717
6 Epidemiology of orofacial clefts (1995-2006) in France (Congenital Malformations of Alsace Registry) [├ępid├ęmiologie des fentes labio-palatines: Exp├ęrience du Registre de malformations cong├ęnitales dŠAlsace entre 1995 et 2006]
Doray, B. and Badila-Timbolschi, D. and Schaefer, E. and Fattori, D. and Monga, B. and Dott, B. and Favre, R. and Kohler, M. and Nisand, I. and Viville, B. and Kauffmann, I. and Bruant-Rodier, C. and Grollemund, B. and Rinkenbach, R. and Astruc, D. and Gasser, B. and Lindner, V. and Marcellin, L. and Flori, E. and Girard-Lemaire, F. and Dollfus, H.
Archives de Pediatrie. 2012; 19(10): 1021-1029
7 Analysis of the coding sequence of the MSX1 and PAX9 genes in patients with the congenital lack of permanent teeth [Analiza sekwencji koduja{ogonek
Mostowska, A. and Biedziak, B. and Jagodziński, P.P.
Dental and Medical Problems. 2012; 49(2): 157-165
8 Detection of orbicularis oris muscle defects in first degree relatives of cleft lip children using ultrasound
Mittal, M. and Maheshwari, N. and Ahlawat, K. and Sharma, V. and Sultan, A. and Chopra, R.
Journal of Indian Society of Pedodontics and Preventive Dentistry. 2012; 30(3): 237-241
9 Developmental Epigenetics of the Murine Secondary Palate
R. S. Seelan,P. Mukhopadhyay,M. M. Pisano,R. M. Greene
ILAR Journal. 2012; 53(3-4): 240
[Pubmed] | [DOI]
10 No Evidence of Association Between 8q24 and Susceptibility to Nonsyndromic Cleft Lip With or Without Palate in Japanese Population
Masanori Hikida,Masayoshi Tsuda,Akira Watanabe,Akira Kinoshita,Sadanori Akita,Akiyoshi Hirano,Takeshi Uchiyama,Koh-ichiro Yoshiura
The Cleft Palate-Craniofacial Journal. 2012; 49(6): 714
[Pubmed] | [DOI]
11 ╔pidÚmiologie des fentes labio-palatinesá: expÚrience du Registre de malformations congÚnitales dĺAlsace entre 1995áet 2006
B. Doray,D. Badila-Timbolschi,E. Schaefer,D. Fattori,B. Monga,B. Dott,R. Favre,M. Kohler,I. Nisand,B. Viville,I. Kauffmann,C. Bruant-Rodier,B. Grollemund,R. Rinkenbach,D. Astruc,B. Gasser,V. Lindner,L. Marcellin,E. Flori,F. Girard-Lemaire,H. Dollfus
Archives de PÚdiatrie. 2012; 19(10): 1021
[Pubmed] | [DOI]
12 Polymorphisms in CHDH gene and the risk of tooth agenesis
Adrianna Mostowska, Barbara Biedziak, Izabella Dunin-Wilczynska, Anna Komorowska, Pawel P. Jagodzinski
Birth Defects Research Part A Clinical and Molecular Teratology. 2011; 91(3): 169
[VIEW] | [DOI]
13 Polymorphic variants of genes related to arginine metabolism and the risk of orofacial clefts
Kamil K. Hozyasz,Adrianna Mostowska,Piotr Wojcicki,Margarita Lianeri,Pawel P. Jagodzinski
Archives of Oral Biology. 2010; 55(11): 861
[Pubmed] | [DOI]
14 The search for risk factors that contribute to the etiology of non-syndromic cleft lip with or without cleft palate (CL/P) in the Polish population [Poszukiwanie czynnik├│w ryzyka, kt├│re moga╠ž wp┼éywa─ç na powstawanie niezespo┼éowych rozszczep├│w wargi po┼éa╠žczonych, lub te┼╝ nie, z rozszczepem podniebienia (CL/P) w populacji polskiej. Przegla╠žd cyklu publikacji]
Hozyasz, K.K.
Pediatria Polska. 2010; 85(6): 609-623
15 Polymorphisms located in the region containing BHMT and BHMT2 genes as maternal protective factors for orofacial clefts
Mostowska, A. and Hozyasz, K.K. and Biedziak, B. and Misiak, J. and Jagodzinski, P.P.
European Journal of Oral Sciences. 2010; 118(4): 325-332
16 The search for risk factors that contribute to the etiology of non-syndromic cleft lip with or without cleft palate (CL/P) in the Polish population
Kamil K. Hozyasz
Pediatria Polska. 2010; 85(6): 609
[VIEW] | [DOI]
17 Polymorphic variants of genes related to arginine metabolism and the risk of orofacial clefts
Hozyasz, K.K., Mostowska, A., Wojcicki, P., Lianeri, M., Jagodzinski, P.P.
Archives of Oral Biology. 2010; 55(11): 861-866
18 Association between genetic variants of reported candidate genes or regions and risk of cleft lip with or without cleft palate in the polish population
Adrianna Mostowska, Kamil K. Hozyasz, Piotr Wojcicki, Barbara Biedziak, Patrycja Paradowska, Pawel P. Jagodzinski
Birth Defects Research Part A Clinical and Molecular Teratology. 2010; 88(7): 538
[VIEW] | [DOI]
19 Polymorphisms located in the region containing BHMT and BHMT2 genes as maternal protective factors for orofacial clefts : BHMT and BHMT2 gene variants and NCL/P
Adrianna Mostowska, Kamil K. Hozyasz, Barbara Biedziak, Jan Misiak, Pawel P. Jagodzinski
European Journal Of Oral Sciences. 2010; 118(4): 325
[VIEW] | [DOI]


Print this article  Email this article
Previous article Next article


Site Map  |  Home  |  Contact Us  |  Feedback  |  Copyright and Disclaimer
Online since 11th March '04
Published by Wolters Kluwer - Medknow