CC BY-NC-ND 4.0 · Indian J Plast Surg 2009; 42(01): 068-081
DOI: 10.1055/s-0039-1699316
Review Article
Association of Plastic Surgeons of India

Current concepts in genetics of nonsyndromic clefts

Jyotsna Murthy
Department of Plastic Surgery and Sri Ramachandra Medical College, Chennai, India
,
L. V. K. S. Bhaskar
1  Department of Biomedical Sciences, Sri Ramachandra Medical College, Chennai, India
› Author Affiliations
Further Information

Publication History

Publication Date:
15 January 2020 (online)

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.

 
  • REFERENCES

  • 1 Schutte BC, Murray JC. The many faces and factors of orofacial clefts. Hum Mol Genet 1999;8:1853-9.
  • 2 Murray JC. Face facts: Genes, environment, and clefts. Am J Hum Genet 1995;57:227-32.
  • 3 Gaspar DA, Matioli SR, de Cássia Pavanello R, Araoejo 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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..
  • 14 Carreno H, Paredes M, Téllez 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.
  • 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.
  • 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.
  • 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.
  • 18 Wyszynski DF, Maestri N, Lewanda AF, McIntosh I, Smith EA, García-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.
  • 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.
  • 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.
  • 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.
  • 22 Vieira AR, Avila JR, Daack-Hirsch S, Dragan E, Félix TM, Rahimov F, et al. Medical sequencing of candidate genes for nonsyndromic cleft lip and palate. PLoS Genet 2005;1:e64.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 28 Brunner HG, Hamel BC, Bokhoven Hv H. P63 gene mutations and human developmental syndromes. Am J Med Genet 2002;112:284-90.
  • 29 Leoyklang P, Siriwan P, Shotelersuk V. A mutation of the p63 gene in non-syndromic cleft lip. J Med Genet 2006;43:e28.
  • 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.
  • 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.
  • 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.
  • 33 Wyszynski DF, Wu T. Prenatal and perinatal factors associated with isolated oral clefting. Cleft Palate Craniofac J 2002;39:370-5.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 47 Marazita ML, Field LL, Tunçbilek G, Cooper ME, Goldstein T, Gürsu 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.
  • 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.
  • 49 Lander E, Kruglyak L. Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nat Genet 1995;11:241-7.
  • 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.
  • 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.
  • 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.
  • 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.
  • 54 Mitchell LE. Genetic epidemiology of birth defects: Nonsyndromic cleft lip and neural tube defects. Epidemiol Rev 1997;19:61-8.
  • 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.
  • 56 Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet 2003;361:598-604.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 67 Dode C, Levilliers J, Dupont JM, De Paepe A, Le Dû N, Soussi-Yanicostas N, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003;33:463-5.
  • 68 Dode C, Hardelin JP. Kallmann syndrome: Fibroblast growth factor signaling insufficiency? J Mol Med 2004;82:725-34.
  • 69 Dodé 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.
  • 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.
  • 71 Sozen MA, Suzuki K, Tolarova MM, Bustos T, Fernñndez 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.
  • 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.
  • 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.
  • 74 van Bokhoven H, Brunner HG. Splitting p63. Am J Hum Genet 2002;71:1-13.
  • 75 Braybrook C, Lisgo S, Doudney K, Henderson D, Marçano 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.
  • 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.
  • 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.
  • 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.
  • 79 Castanet M, Park SM, Smith A, Bost M, Léger 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 91 Warkany J, Nelson RS. Appearance of skeletal abonormalities in the offspring of rats reared on a deficient diet. Science 1940;92:383-4.
  • 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.
  • 93 Shaw GM, Lammer EJ. Maternal periconceptional alcohol consumption and risk for orofacial clefts. J Pediatr 1999;134: 298-303.
  • 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.
  • 95 Walker BE. Induction of cleft palate in rabbits by several glucocorticoids. Proc Soc Exp Biol Med 1967;125:1281-4.
  • 96 Walker BE. Induction of cleft palate in rats with antiinflammatory drugs. Teratology 1971;4:39-42.
  • 97 Marazita ML, Jaskoll T, Melnick M. Corticosteroid-induced cleft palate in short-ear mice. J Craniofac Genet Dev Biol 1988;8: 47-51.
  • 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.
  • 99 Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:242-4.
  • 100 Rodríguez-Pinilla E, Martínez-Frías ML. Corticosteroids during pregnancy and oral clefts: A case-control study. Teratology 1998;58:2-5.
  • 101 Ericson A, Källén B, Westerholm P. Cigarette smoking as an etiologic factor in cleft lip and palate. Am J Obstet Gynecol 1979;135:348-51.
  • 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.
  • 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.
  • 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.
  • 105 Wyszynski DF, Duffy DL, Beaty TH. Maternal cigarette smoking and oral clefts: A meta-analysis. Cleft Palate Craniofac J 1997;34:206-10.
  • 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.
  • 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.
  • 108 Jones KL, Smith DW, Ulleland CN, Streissguth P. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973;1:1267-71.
  • 109 Abel EL. Fetal alcohol syndrome: The American paradox. Alcohol Alcohol 1998;33:195-201.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 118 Rozen R. Genetic predisposition to hyperhomocysteinemia: Deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost 1997;78:523-6.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 131 Jara L, Blanco R, Chiffelle I, Palomino H, Carreño 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 136 Albuisson J, POEcheux 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 143 Brandalize AP, Bandinelli E, Borba JB, Félix TM, Roisenberg I, Schüler-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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.