Cleft lip and palate genetics and application in early embryological development

ABSTRACT

The development of the head involves the interaction of several cell populations and coordination of cell signalling pathways, which when disrupted can cause defects such as facial clefts. This review concentrates on genetic contributions to facial clefts with and without cleft palate (CP). An overview of early palatal development with emphasis on muscle and bone development is blended with the effects of environmental insults and known genetic mutations that impact human palatal development. An extensive table of known genes in syndromic and non-syndromic CP, with or without cleft lip (CL), is provided. We have also included some genes that have been identified in environmental risk factors for CP/L. We include primary and review references on this topic.

KEY WORDS

Cleft lip/palate - Human/murine palate genetics - Palate development

• REFERENCES

• 1 Ferguson MW. Palate development. Develop 1988;103:41-60.
• 2 Christensen K, Juel K, Herskind AM, Murray JC. Long term follow up study of survival associated with cleft lip and palate at birth. BMJ 2004;328:1405.
• 3 Fogh-Andersen P. Epidemiology and etiology of clefts. In: Bergsma D, editor. Birth defects: Original article series. Baltimore: Williams and Wilkins Co.; 1971.
• 4 Slavkin HC. Incidence of cleft lips, palates rising. J Am Dent Assoc 1992;123:61-5.
• 5 Murray JC. Gene/environment causes of cleft lip and/or palate. [review] [122 refs]. Clinical Genetics 2002;61:248-56.
• 6 Gritli-Linde A. The etiopathogenesis of cleft lip and cleft palate usefulness and caveats of mouse models. Curr Top Dev Biol 2008;84:37-138.
• 7 Gritli-Linde A. Molecular control of secondary palate development. Developmental Biology 2007; 301:309-26.
• 8 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.
• 9 Chai Y, Maxson RE, Jr. Recent advances in craniofacial morphogenesis. Dev Dyn 2006;235:2353-75.
• 10 Wyszynski DF, Duffy DL, Beaty TH. Maternal cigarette smoking and oral clefts: A meta-analysis. Cleft Palate Craniofac J 1997;34:206-10.
• 11 Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (a80g), and risk of spina bifida. Am J Med Genet 2002;108:1-6.
• 12 Boot MJ, Steegers-Theunissen RP, Poelmann RE, Van Iperen L, Lindemans J, Gittenberger-de Groot AC. Folic acid and homocysteine affect neural crest and neuroepithelial cell outgrowth and differentiation in vitro. Dev Dyn 2003;227:301-8.
• 13 Briggs RM. Vitamin supplementation as a possible factor in the incidence of cleft lip/palate deformities in humans. Clin Plast Surg 1976;3:647-52.
• 14 Finnell RH, Shaw GM, Lammer EJ, Brandl KL, Carmichael SL, Rosenquist TH. Gene-nutrient interactions: Importance of folates and retinoids during early embryogenesis. Toxicol Appl Pharmacol 2004;198:75-85.
• 15 Itikala PR, Watkins ML, Mulinare J, Moore CA, Liu Y. Maternal multivitamin use and orofacial clefts in offspring. Teratology 2001; 63:79-86.
• 16 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.
• 17 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 A 2005;135:274-7.
• 18 Tang LS, Santillano DR, Wlodarczyk BJ, Miranda RC, Finnell RH. Role of folbp1 in the regional regulation of apoptosis and cell proliferation in the developing neural tube and craniofacies. Am J Med Genet C Semin Med Genet 2005;135:48-58.
• 19 Lammer EJ, Shaw GM, Iovannisci DM, Van Waes J, Finnell RH. Maternal smoking and the risk of orofacial clefts: Susceptibility with nat1 and nat2 polymorphisms. Epidemiology 2004;15:150-6.
• 20 Shaw GM, Zhu H, Lammer EJ, Yang W, Finnell RH. Genetic variation of infant reduced folate carrier (a80g) and risk of orofacial and conotruncal heart defects. Am J Epidemiol 2003;158:747-52.
• 21 Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat 1995;154:8-20.
• 22 Kang P, Svoboda KK. Epithelial-mesenchymal transformation during craniofacial development. J Dent Res 2005;84:678-90.
• 23 Nawshad A. Palatal seam disintegration: To die or not to die? That is no longer the question. Dev Dyn 2008;237:2643-56.
• 24 Shuler CF. Programmed cell death and cell transformation in craniofacial development. Crit Rev Oral Biol Med 1995;6:202-17.
• 25 Murray JC, Schutte BC. Cleft palate: Players, pathways, and pursuits. J Clin Invest 2004;113:1676-8.
• 26 Yu W, Ruest L, Svoboda K. Regulation of epithelial-mesenchymal transition in palatal fusion. Exp Biol Med (Maywood) 2009; 234:483-91.
• 27 Britto JA, Evans RD, Hayward RD, Jones BM. Toward pathogenesis of Apert cleft palate: Fgf, fgfr, and tgf beta genes are differentially expressed in sequential stages of human palatal shelf fusion. Cleft Palate Craniofac J 2002;39:332-40.
• 28 Shi M, Wehby GL, Murray JC. Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects. Birth Defects Res C Embryo Today 2008;84:16-29.
• 29 Shuler CF, Halpern DE, Guo Y, Sank AC. Medial edge epithelium fate traced by cell lineage analysis during epithelial-mesenchymal transformation in vivo. Dev Biol 1992;154:318-30.
• 30 Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 1995;154:8-20.
• 31 Kaartinen V, Cui XM, Heisterkamp N, Groffen J, Shuler CF. Transforming growth factor-beta3 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane. Dev Dyn 1997;209:255-60.
• 32 Kang Y, Massague J. Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell 2004;118:277-9.
• 33 Nawshad A, Hay ED. Tgfbeta3 signaling activates transcription of the lef1 gene to induce epithelial mesenchymal transformation during mouse palate development. J Cell Biol 2003;163:1291-301.
• 34 Nawshad A, LaGamba D, Hay ED. Transforming growth factor beta (TGFbeta) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol 2004;49:675-89.
• 35 Sun W, Vincent S, Settleman J, Johnson GL. Mek kinase 2 binds and activates protein kinase c-related kinase 2. Bifurcation of kinase regulatory pathways at the level of an mapk kinase kinase. J Biol Chem 2000;275:24421-8.
• 36 LaGamba D, Nawshad A, Hay ED. Microarray analysis of gene expression during epithelial-mesenchymal transformation. Dev Dyn 2005;234:132-42.
• 37 Cuervo R, Covarrubias L. Death is the major fate of medial edge epithelial cells and the cause of basal lamina degradation during palatogenesis. Develop 2004;131:15-24.
• 38 Cuervo R, Valencia C, Chandraratna RA, Covarrubias L. Programmed cell death is required for palate shelf fusion and is regulated by retinoic acid. Dev Biol 2002;245:145-56.
• 39 Mori C, Nakamura N, Okamoto Y, Osawa M, Shiota K. Cytochemical identification of programmed cell death in the fusing fetal mouse palate by specific labelling of DNA fragmentation. Anat Embryol (Berl) 1994;190:21-8.
• 40 Taniguchi K, Sato N, Uchiyama Y. Apoptosis and heterophagy of medial edge epithelial cells of the secondary palatine shelves during fusion. Arch Histol Cytol 1995;58:191-203.
• 41 Carette MJ, Ferguson MW. The fate of medial edge epithelial cells during palatal fusion in vitro: An analysis by dii labelling and confocal microscopy. Development 1992;114:379-88.
• 42 Jin J-Z, Ding J. Analysis of cell migration, transdifferentiation and apoptosis during mouse secondary palate fusion. Development 2006;133:3341-7.
• 43 Martinez-Alvarez C, Blanco MJ, Perez R, Rabadan MA, Aparicio M, Resel E, et al. Snail family members and cell survival in physiological and pathological cleft palates. Dev Biol 2004;265:207-18.
• 44 Sun D, Baur S, Hay ED. Epithelial-mesenchymal transformation is the mechanism for fusion of the craniofacial primordia involved in morphogenesis of the chicken lip. Dev Biol 2000;228:337-49.
• 45 Rice R, Spencer-Dene B, Connor EC, Gritli-Linde A, McMahon AP, Dickson C, et al. Disruption of fgf10/fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate.[see comment]. J Clin Invest 2004;113:1692-700.
• 46 Rice R, Thesleff I, Rice DP. Regulation of Twist, Snail, and Id1 is conserved between the developing murine palate and tooth. Dev Dyn 2005;234:28-35.
• 47 Nie X, Luukko K, Kettunen P. FGF signalling in craniofacial development and developmental disorders. Oral Dis 2006;12:102-11.
• 48 Hilliard SA, Yu L, Gu S, Zhang Z, Chen YP. Regional regulation of palatal growth and patterning along the anterior-posterior axis in mice. J Anat 2005;207:655-67.
• 49 Yu L, Gu S, Alappat S, Song Y, Yan M, Zhang X, et al. Shox2-deficient mice exhibit a rare type of incomplete clefting of the secondary palate. Development 2005;132:4397-406.
• 50 Alappat SR, Zhang Z, Suzuki K, Zhang X, Liu H, Jiang R, et al. The cellular and molecular etiology of the cleft secondary palate in fgf10 mutant mice. Dev Biol 2005;277:102-13.
• 51 Braybrook C, Doudney K, Marcano AC, Arnason A, Bjornsson A, Patton MA, et al. The t-box transcription factor gene tbx22 is mutated in x-linked cleft palate and ankyloglossia. Nat Genet 2001;29:179-83.
• 52 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.
• 53 Wong FK, Hagg U. An update on the aetiology of orofacial clefts. Hong Kong Med J 2004;10:331-6.
• 54 Ferguson MW. Palatal shelf elevation in the wistar rat fetus. J Anat 1978;125:555-77.
• 55 Brinkley LL, Morris-Wiman J, Brinkley LL, Morris-Wiman J. The role of extracellular matrices in palatal shelf closure. Curr Top Dev Biol 1984;19:17-36.
• 56 Brinkley LL, Morris-Wiman J, Brinkley LL, Morris-Wiman J. Effects of chlorcyclizine-induced glycosaminoglycan alterations on patterns of hyaluronate distribution during morphogenesis of the mouse secondary palate. Development 1987;100:637-40.
• 57 Kist R, Greally E, Peters H. Derivation of a mouse model for conditional inactivation of pax9. Genesis 2007;45:460-4.
• 58 Peters H, Neubuser A, Kratochwil K, Balling R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev 1998;12:2735-47.
• 59 Szeto DP, Rodriguez-Esteban C, Ryan AK, O'Connell SM, Liu F, Kioussi C, et al. Role of the bicoid-related homeodomain factor pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev 1999;13:484-94.
• 60 Gao Y, Lan Y, Ovitt CE, Jiang R. Functional equivalence of the zinc finger transcription factors osr1 and osr2 in mouse development. Dev Biol 2009;328; 200-9.
• 61 Wee EL, Zimmerman EF. Involvement of GABA in palate morphogenesis and its relation to diazepam teratogenesis in two mouse strains. Teratology 1983;28:15-22.
• 62 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.
• 63 Varju P, Katarova Z, Madarasz E, Szabo G. GABA signalling during development: New data and old questions. Cell Tissue Res 2001;305:239-46.
• 64 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.
• 65 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 U S A 1997;94:11451-5.
• 66 Yanagisawa H, Clouthier DE, Richardson JA, Charite J, Olson EN. Targeted deletion of a branchial arch-specific enhancer reveals a role of hand in craniofacial development. Development 2003;130:1069-78.
• 67 Barbosa AC, Funato N, Chapman S, McKee MD, Richardson JA, Olson EN, et al. Hand transcription factors cooperatively regulate development of the distal midline mesenchyme. Dev Biol 2007;310:154-68.
• 68 Fitchett JE, Hay ED. Medial edge epithelium transforms to mesenchyme after embryonic palatal shelves fuse. Dev Biol 1989;131:455-74.
• 69 Montenegro MA, Rojas M, Dominguez S, Vergara A. Cytokeratin, vimentin and e-cadherin immunodetection in the embryonic palate in two strains of mice with different susceptibility to glucocorticoid-induced clefting. J Craniofac Genet Dev Biol 2000;20:137-43.
• 70 Vaziri Sani F, Hallberg K, Harfe BD, McMahon AP, Linde A, Gritli-Linde A. Fate-mapping of the epithelial seam during palatal fusion rules out epithelial-mesenchymal transformation. Dev Biol 2005;285:490-5.
• 71 Yu W, Kamara H, Svoboda KH. The role of twist during palate development. Dev Dyn 2008;237:2716-25.
• 72 Frebourg T, Oliveira C, Hochain P, Karam R, Manouvrier S, Graziadio C, et al. Cleft lip/palate and cdh1/e-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet 2006;43:138-42.
• 73 Cui XM, Shiomi N, Chen J, Saito T, Yamamoto T, Ito Y et al. Overexpression of smad2 in tgf-beta3-null mutant mice rescues cleft palate. Dev Biol 2005;278; 193-202.
• 74 Fitzpatrick DR, Denhez F, Kondaiah P, Akhurst RJ. Differential expression of tgf beta isoforms in murine palatogenesis. Development 1990;109:585-95.
• 75 Pelton RW, Dickinson ME, Moses HL, Hogan BL. In situ hybridization analysis of tgf beta 3 rna expression during mouse development: Comparative studies with tgf beta 1 and beta 2. Development 1990;110:609-20.
• 76 Pelton RW, Hogan BL, Miller DA, Moses HL. Differential expression of genes encoding tgfs beta 1, beta 2, and beta 3 during murine palate formation. Dev Biol 1990;141:456-60.
• 77 Schock F, Perrimon N. Molecular mechanisms of epithelial morphogenesis. Annu Rev Cell Dev Biol 2002;18:463-93.
• 78 Blavier L, Lazaryev A, Groffen J, Heisterkamp N, DeClerck YA, Kaartinen V. Tgf-beta3-induced palatogenesis requires matrix metalloproteinases. Mol Biol Cell 2001;12:1457-66.
• 79 Kaartinen V, Haataja L, Nagy A, Heisterkamp N, Groffen J. TGFbeta3-induced activation of rhoa/rho-kinase pathway is necessary but not sufficient for epithelio-mesenchymal transdifferentiation: Implications for palatogenesis. Int J Mol Med 2002;9:563-70.
• 80 Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, et al. Abnormal lung development and cleft palate in mice lacking tgf-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 1995;11:415-21.
• 81 Miettinen PJ, Chin JR, Shum L, Slavkin HC, Shuler CF, Derynck R, et al. Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure. Nature Genetics 1999;22:69-73.
• 82 Sperber G, Craniofacial development. Hamilton and London: BC Decker Inc; 2001.
• 83 Mori-Akiyama Y, Akiyama H, Rowitch DH, de Crombrugghe B. Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest. Proc Natl Acad Sci U S A 2003;100:9360-5.
• 84 Kjaer I. Human prenatal palatal shelf elevation related to craniofacial skeletal maturation. Eur J Orthod 1992;14:26-30.
• 85 Okano J, Suzuki S, Shiota K. Regional heterogeneity in the developing palate: Morphological and molecular evidence for normal and abnormal palatogenesis. Congenit Anom (Kyoto) 2006;46:49-54.
• 86 Kerrigan JJ, Mansell JP, Sengupta A, Brown N, Sandy JR. Palatogenesis and potential mechanisms for clefting. J R Coll Surg Edinb 2000;45:351-8.
• 87 Iwasaki M, Le AX, Helms JA. Expression of Indian hedgehog, bone morphogenetic protein 6 and gli during skeletal morphogenesis. 1997;69:197-202.
• 88 Adab K, Sayne JR, Carlson DS, Opperman LA. Tgf-beta1, tgf-beta2, tgf-beta3 and msx2 expression is elevated during frontonasal suture morphogenesis and during active postnatal facial growth. Orthod Craniofac Res 2002;5; 227-37
• 89 Adab K, Sayne JR, Carlson DS, Opperman LA. Nasal capsular cartilage is required for rat transpalatal suture morphogenesis. Differentiation 2003;71:496-505.
• 90 Opperman LA. Cranial sutures as intramembranous bone growth sites. Dev Dyn 2000;219:472-85.
• 91 Vij K, Mao JJ. Geometry and cell density of rat craniofacial sutures during early postnatal development and upon in vivo cyclic loading. Bone 2006;38:722-30.
• 92 Liu C, Song R, Song Y. A serial histological study on suture expansion osteogenesis for cleft palate closure. Zhonghua Zheng Xing Wai Ke Za Zhi 2000;16:43-5.
• 93 Hou B, Fukai N, Olsen BR. Mechanical force-induced midpalatal suture remodeling in mice. Bone 2007;40:1483-93.
• 94 Takahashi I, Mizoguchi I, Nakamura M, Sasano Y, Saitoh S, Kagayama M, et al. Effects of expansive force on the differentiation of midpalatal suture cartilage in rats. Bone 1996;18:341-8.
• 95 Kobayashi ET, Hashimoto F, Kobayashi Y, Sakai E, Miyazaki Y, Kamiya T, et al. Force-induced rapid changes in cell fate at midpalatal suture cartilage of growing rats. J Dent Res 1999;78: 1495-504.
• 96 Cowan CM, Cheng S, Ting K, Soo C, Walder B, Wu B, et al. Nell-1 induced bone formation within the distracted intermaxillary suture. Bone 2006;38:48-58.
• 97 Sawada M, Shimizu N. Stimulation of bone formation in the expanding mid-palatal suture by transforming growth factor-beta 1 in the rat. Eur J Orthod 1996;18:169-79.
• 98 Akita S, Hirano A. Surgical modifications for microform cleft lip repairs. J Craniofac Surg 2005;16:1106-10.
• 99 Neiswanger K, Weinberg SM, Rogers CR, Brandon CA, Cooper ME, Bardi KM, et al. Orbicularis oris muscle defects as an expanded phenotypic feature in nonsyndromic cleft lip with or without cleft palate. Am J Med Genet A 2007;143:1143-9.
• 100 Jiang R, Bush JO, Lidral AC. Development of the upper lip: Morphogenetic and molecular mechanisms. Dev Dyn 2006;235:1152-66.
• 101 Marazita ML. Subclinical features in non-syndromic cleft lip with or without cleft palate (cl/p): Review of the evidence that subepithelial orbicularis oris muscle defects are part of an expanded phenotype for cl/p. Orthod Craniofac Res 2007;10:82-7.
• 102 Gosain AK, Conley SF, Marks S, Larson DL. Submucous cleft palate: Diagnostic methods and outcomes of surgical treatment. Plast Reconstr Surg 1996;97:1497-509.
• 103 Boorman JG, Varma S, Ogilvie CM. Velopharyngeal incompetence and chromosome 22q11 deletion. Lancet 2001;357:774.
• 104 Sweeney L. Basic concepts in embryology: A student's survival guide. McGraw-Hill Professional; 1998. p. 443.
• 105 Trotman CA, Hou D, Burdi AR, Cohen SR, Carlson DS. Histomorphologic analysis of the soft palate musculature in prenatal cleft and noncleft a/jax mice. Cleft Palate Craniofac J 1995;32:455-62.
• 106 Weinberg SM, Neiswanger K, Martin RA, Mooney MP, Kane AA, Wenger SL, et al. The Pittsburgh oral-facial cleft study: Expanding the cleft phenotype. Background and justification. Cleft Palate Craniofac J 2006;43:7-20.
• 107 Pauws E, Stanier P. Fgf signalling and sumo modification: New players in the aetiology of cleft lip and/or palate. Trends Genet 2007;23:631-40.
• 108 Zhang FP, Mikkonen L, Toppari J, Palvimo JJ, Thesleff I, Janne OA. Sumo-1 function is dispensable in normal mouse development. Mol Cell Biol 2008;28:5381-90.
• 109 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.
• 110 Andreou AM, Pauws E, Jones MC, Singh MK, Bussen M, Doudney K, et al. Tbx22 missense mutations found in patients with x-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. Am J Hum Genet 2007;81:700-12.
• 111 Lan Y, Ovitt CE, Cho ES, Maltby KM, Wang Q, Jiang R. Odd-skipped related 2 (osr2) encodes a key intrinsic regulator of secondary palate growth and morphogenesis. Development 2004;131:3207-16.
• 112 Ferguson MW, Honig LS, Slavkin HC. Differentiation of cultured palatal shelves from alligator, chick, and mouse embryos. Anat Rec 1984;209:231-49.
• 113 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.
• 114 Kreiborg S, Cohen MM Jr. The oral manifestations of Apert syndrome. J Craniofac Genet Dev Biol 1992;12:41-8.
• 115 Martelli H Jr, Paranaiba LM, de Miranda RT, Orsi J Jr, Coletta RD. Apert syndrome: Report of a case with emphasis on craniofacial and genetic features. Pediatr Dent 2008;30:464-8.
• 116 Park WJ, Theda C, Maestri NE, Meyers GA, Fryburg JS, Dufresne C, et al. Analysis of phenotypic features and fgfr2 mutations in apert syndrome. Am J Hum Genet 1995;57:321-8.
• 117 Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, et al. Apert syndrome results from localized mutations of fgfr2 and is allelic with Crouzon syndrome. Nat Genet 1995;9:165-72.
• 118 Moloney DM, Slaney SF, Oldridge M, Wall SA, Sahlin P, Stenman G, et al. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet 1996;13:48-53.
• 119 Castanet M, Park SM, Smith A, Bost M, Leger 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.
• 120 Clifton-Bligh RJ, Wentworth JM, Heinz P, Crisp MS, John R, Lazarus JH, et al. Mutation of the gene encoding human ttf-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 1998;19:399-401.
• 121 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.
• 122 Kallen B, Mastroiacovo P, Robert E. Major congenital malformations in Down syndrome. Am J Med Genet 1996;65: 160-6.
• 123 Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of eec syndrome. Cell 1999;99:143-53.
• 124 McGrath JA, Duijf PH, Doetsch V, Irvine AD, de Waal R, Vanmolkot KR, et al. Hay-Wells syndrome is caused by heterozygous missense mutations in the sam domain of p63. Hum Mol Genet 2001;10: 221-9.
• 125 Abel EL. Fetal alcohol syndrome: A cautionary note. Curr Pharm Des 2006;12:1521-9.
• 126 Green ML, Singh AV, Zhang Y, Nemeth KA, Sulik KK, Knudsen TB. Reprogramming of genetic networks during initiation of the fetal alcohol syndrome. Dev Dyn 2007;236:613-31.
• 127 Seki M, Yoshida K, Kashimura M. [a case of fetal alcohol effects with orofacial cleft]. Nihon Arukoru Yakubutsu Igakkai Zasshi 2005;40:137-43.
• 128 Wattendorf DJ, Muenke M. Fetal alcohol spectrum disorders. Am Fam Physician 2005;72:279-82, 85.
• 129 Kokavec R. Goldenhar syndrome with various clinical manifestations. Cleft Palate Craniofac J 2006;43:628-34.
• 130 Vilkki SK, Hukki J, Nietosvaara Y, Hurmerinta K, Suominen E. Microvascular temporomandibular joint and mandibular ramus reconstruction in hemifacial microsomia. J Craniofac Surg 2002;13:809-15.
• 131 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.
• 132 Dode C, Fouveaut C, Mortier G, Janssens S, Bertherat J, Mahoudeau J, et al. Novel fgfr1 sequence variants in Kallmann syndrome, and genetic evidence that the fgfr1c isoform is required in olfactory bulb and palate morphogenesis. Hum Mutat 2007;28:97-8.
• 133 Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, et al. Loss-of-function mutations in fgfr1 cause autosomal dominant Kallmann syndrome.[see comment]. Nature Genetics 2003;33:463-5.
• 134 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.
• 135 Prows CA, Bender PL. Beyond Pierre Robin sequence. Neonatal Netw 1999;18:13-9.
• 136 Cole A, Lynch P, Slator R. A new grading of Pierre Robin sequence. Cleft Palate Craniofac J 2008;45:603-6.
• 137 Muenke M. The pit, the cleft and the web. Nat Genet 2002;32:219-20.
• 138 Wassif CA, Maslen C, Kachilele-Linjewile S, Lin D, Linck LM, Connor WE, et al. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet 1998;63:55-62.
• 139 Snead MP, Yates JR. Clinical and molecular genetics of Stickler syndrome. J Med Genet 1999;36:353-9.
• 140 Wilkin DJ, Mortier GR, Johnson CL, Jones MC, de Paepe A, Shohat M, et al. Correlation of linkage data with phenotype in eight families with Stickler syndrome. Am J Med Genet 1998;80:121-7.
• 141 Dixon J, Jones NC, Sandell LL, Jayasinghe SM, Crane J, Rey JP, et al. Tcof1/treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proc Natl Acad Sci U S A 2006;103:13403-8.
• 142 Valdez BC, Henning D, So RB, Dixon J, Dixon MJ. The Treacher Collins syndrome (tcof1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor. Proc Natl Acad Sci U S A 2004;101:10709-14.
• 143 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.
• 144 Cuneo BF. 22q11.2 deletion syndrome: Digeorge, velocardiofacial, and conotruncal anomaly face syndromes. Curr Opin Pediatr 2001;13:465-72.
• 145 Moreno F, Zuazo E, Gonzalez S, Bereciartu P. 22q11 deletion syndrome: An expanding phenotype.. Neurologia 2009;24: 69-71.
• 146 Sanlaville D, Etchevers HC, Gonzales M, Martinovic J, Clement-Ziza M, Delezoide AL, et al. Phenotypic spectrum of CHARGE syndrome in fetuses with chd7 truncating mutations correlates with expression during human development. J Med Genet 2006;43: 211-7.
• 147 Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, et al. Mutations in a new member of the chromodomain gene family cause charge syndrome. Nat Genet 2004;36:955-7.
• 148 Schuffenhauer S, Leifheit HJ, Lichtner P, Peters H, Murken J, Emmerich P. De novo deletion (14)(q11.2q13) including pax9: Clinical and molecular findings. J Med Genet 1999;36:233-6.
• 149 Abidi FE, Miano MG, Murray JC, Schwartz CE. A novel mutation in the phf8 gene is associated with x-linked mental retardation with cleft lip/cleft palate. Clin Genet 2007;72:19-22.
• 150 Ming JE, Kaupas ME, Roessler E, Brunner HG, Golabi M, Tekin M, et al. Mutations in patched-1, the receptor for sonic hedgehog, are associated with holoprosencephaly. Hum Genet 2002;110:297-301.
• 151 Ribeiro LA, Murray JC, Richieri-Costa A. Ptch mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal mri. Am J Med Genet A 2006;140:2584-6.
• 152 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.
• 153 Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, et al. Role of tbx1 in human del22q11.2 syndrome. Lancet 2003;362:1366-73.
• 154 Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in tgfbr1 or tgfbr2. Nature Genetics 2005;37:275-81.
• 155 Hines RN, McCarver DG. The ontogeny of human drug-metabolizing enzymes: Phase I oxidative enzymes. J Pharmacol Exp Ther 2002;300:355-60.
• 156 Stoilov I, Jansson I, Sarfarazi M, Schenkman JB. Roles of cytochrome p450 in development. Drug Metabol Drug Interact 2001;18: 33-55.
• 157 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.
• 158 An S, Dickens MA, Bleu T, Hallmark OG, Goetzl EJ. Molecular cloning of the human edg2 protein and its identification as a functional cellular receptor for lysophosphatidic acid. Biochem Biophys Res Commun 1997;231: 619-22.
• 159 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.
• 160 Hartsfield JK Jr, Hickman TA, Everett ET, Shaw GM, Lammer EJ, Finnell RA. Analysis of the ephx1 113 polymorphism and gstm1 homozygous null polymorphism and oral clefting associated with maternal smoking. Am J Med Genet 2001;102:21-4.
• 161 Hozyasz KK, Mostowska A, Surowiec Z, Jagodzinski PP. [genetic polymorphisms of gstm1 and gstt1 in mothers of children with isolated cleft lip with or without cleft palate]. Przegl Lek 2005;62:1019-22.
• 162 Landi S. Mammalian class theta gst and differential susceptibility to carcinogens: A review. Mutat Res 2000;463:247-83.
• 163 Raijmakers MT, Steegers EA, Peters WH. Glutathione s-transferases and thiol concentrations in embryonic and early fetal tissues. Hum Reprod 2001;16:2445-50.
• 164 Sim E, Payton M, Noble M, Minchin R. An update on genetic, structural and functional studies of arylamine n-acetyltransferases in eucaryotes and procaryotes. Hum Mol Genet 2000;9:2435-41.
• 165 Smelt VA, Upton A, Adjaye J, Payton MA, Boukouvala S, Johnson N, et al. Expression of arylamine n-acetyltransferases in pre-term placentas and in human pre-implantation embryos. Hum Mol Genet 2000;9:1101-7.
• 166 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.
• 167 Blanton SH, Kolle BS, Hecht JT, Mulliken JB, Martin ER. No evidence supporting mthfr as a risk factor in the development of familial nsclp. Am J Med Genet 2000;92:370-1.
• 168 Botto LD, Yang Q. 5,10-methylenetetrahydrofolate reductase gene variants and congenital anomalies: A huge review. Am J Epidemiol 2000;151:862-77.
• 169 Jugessur A, Wilcox AJ, Lie RT, Murray JC, Taylor JA, Ulvik A, et al. Exploring the effects of methylenetetrahydrofolate reductase gene variants c677t and a1298c on the risk of orofacial clefts in 261 Norwegian case-parent triads. Am J Epidemiol 2003;157:1083-91.
• 170 Shaw GM, Rozen R, Finnell RH, Todoroff K, Lammer EJ. Infant c677t mutation in mthfr, maternal periconceptional vitamin use, and cleft lip. Am J Med Genet 1998;80:196-8.
• 171 Beaty TH, Wang H, Hetmanski JB, Fan YT, Zeiger JS, Liang KY, et al. A case-control study of nonsyndromic oral clefts in Maryland. Ann Epidemiol 2001;11:434-42.
• 172 Pepe G, Camacho Vanegas O, Giusti B, Brunelli T, Marcucci R, Attanasio M, et al. Heterogeneity in world distribution of the thermolabile c677t mutation in 5,10-methylenetetrahydrofolate reductase. Am J Hum Genet 1998;63:917-20.
• 173 Collier AC, Tingle MD, Paxton JW, Mitchell MD, Keelan JA. Metabolizing enzyme localization and activities in the first trimester human placenta: The effect of maternal and gestational age, smoking and alcohol consumption. Hum Reprod 2002;17: 2564-72.
• 174 Shaw GM, Iovannisci DM, Yang W, Finnell RH, Carmichael SL, Cheng S, et al. Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes. Am J Med Genet A 2005;138:21-6.
• 175 Hwang SJ, Beaty TH, Panny SR, Street NA, Joseph JM, Gordon S, et al. Association study of transforming growth factor alpha (tgf alpha) taqi polymorphism and oral clefts: Indication of gene-environment interaction in a population-based sample of infants with birth defects. Am J Epidemiol 1995;141:629-36.
• 176 Maestri NE, Beaty TH, Hetmanski J, Smith EA, McIntosh I, Wyszynski DF, et al. Application of transmission disequilibrium tests to nonsyndromic oral clefts: Including candidate genes and environmental exposures in the models. Am J Med Genet 1997;73:337-44.
• 177 Miettinen PJ, Perheentupa J, Otonkoski T, Lahteenmaki A, Panula P. Egf- and tgf-alpha-like peptides in human fetal gut. Pediatr Res 1989;26:25-30.
• 178 Hwang SJ. Association study of transforming growth factor alpha (tgf alpha) taqi polymorphism and oral clefts: Indication of gene- environment interaction in a population-based sample of infants with birth defects. Amer J Epidem 1992;135:1000-11.
• 179 Mitchell LE, Murray JC, O'Brien S, Christensen K. Evaluation of two putative susceptibility loci for oral clefts in the Danish population. American Journal of Epidemiology 2001;153: 1007-15.
• 180 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.
• 181 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.
• 182 Felix TM, Hanshaw BC, Mueller R, Bitoun P, Murray JC. Chd7 gene and non-syndromic cleft lip and palate. Am J Med Genet A 2006;140:2110-4.
• 183 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.
• 184 Riley BM, Mansilla MA, Ma J, Daack-Hirsch S, Maher BS, Raffensperger LM, et al. Impaired fgf signaling contributes to cleft lip and palate. Proc Natl Acad Sci U S A 2007;104:4512-7.
• 185 Vieira AR, Avila JR, Daack-Hirsch S, Dragan E, Felix TM, Rahimov F, et al. Medical sequencing of candidate genes for nonsyndromic cleft lip and palate. PLoS Genet 2005;1: e64.
• 186 Inoue H, Kayano S, Aoki Y, Kure S, Yamada A, Hata A, et al. Association of the gabrb3 gene with nonsyndromic oral clefts. Cleft Palate Craniofac J 2008;45:261-6.