Unraveling of factors involved in multifactorial diseases is a great challenge. Different approaches can be contemplate and applied to a variety of congenital malformations. In the present investigation TFAP2A has been considered a good candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCLP) aetiology, basing on a sum of considerations. TFAP2A has been seen involved in orofacial development in mice; it is located in the NSCLP candidate region 6p24; it codes for a transcription factor which regulates expression of IRF6, a gene implied in NSCLP; finally, it is embroiled in the branchiooculofacial syndrome, that includes clefting as feature. A family based association analysis was performed with a sample study of 405 NSCLP triads. Evidence of association was obtained with both single marker and haplotype analyses, thus providing a support for TFAP2A in NSCLP aetiology.
MosseyPALittleJ. Epidemiology of oral clefts: An international perspective. In Cleft lip and palate: From origin to treatment DFE W, ed. Oxford University Press. New York, 2002; 127–44.
2.
JugessurAFarliePGKilpatrickN. The genetics of isolated orofacial clefts: From genotypes to subphenotypes. Oral Dis2009; 15:437–53.
3.
ScapoliLPalmieriAMartinelliMPezzettiFCarinciPTognonMCarinciF. Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population. Am J Hum Genet2005; 76:180–3.
4.
BlantonSHCortezAStalSMullikenJBFinnellRHHechtJT. Variation in IRF6 contributes to nonsyndromic cleft lip and palate. Am J Med Genet A2005; 137A:259–62.
5.
MilunskyJMMaherTAZhaoGRobertsAEStalkerHJZoriRTBurchMNClemensMMullikenJBSmithRLinAE. TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet2008; 82:1171–7.
6.
ReiberJSznajerYPosteguilloEGMullerDLyonnetSBaumannCJustW. Additional clinical and molecular analyses of TFAP2A in patients with the Branchio-Oculo-Facial syndrome: Previously reported patient. Am J Med Genet A2010; 152A:2143.
7.
MilunskyJMMaherTMZhaoGWangZMullikenJBChitayatDClemensMStalkerHJBauerMBurchMChenierSCunninghamMLDrackAVJanssensSKarleaAKlattRKiniUKleinOLachmeijerAMMegarbaneAMendelsohnNJMeschinoWSMortierGRParkashSRayCRRobertsARobertsAReardonWSchnurRESmithRSplittMTezcanKWhitefordMLWongDAZoriRLinAE. Genotype-phenotype analysis of the branchio-oculo-facial syndrome. Am J Med Genet A2011; 155A:22–32.
8.
ZhangJHagopian-DonaldsonSSerbedzijaGElsemoreJPlehn-DujowichDMcMahonAPFlavellRAWilliamsT. Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature1996; 381:238–41.
9.
DonnaiDHeatherLJSinclairPThakkerYScamblerPJDixonMJ. Association of autosomal dominant cleft lip and palate and translocation 6p23;9q22.3. Clin Dysmorphol1992; 1:89–97.
10.
DaviesAFStephensRJOlavesenMGHeatherLDixonMJMageeAFlinterFRagoussisJ. Evidence of a locus for orofacial clefting on human chromosome 6p24 and STS content map of the region. Hum Mol Genet1995; 4:121–8.
11.
RahimovFMarazitaMLViselACooperMEHitchlerMJRubiniMDomannFEGovilMChristensenKBilleCMelbyeMJugessurALieRTWilcoxAJFitzpatrickDRGreenEDMosseyPALittleJSteegers-TheunissenRPPennacchioLASchutteBCMurrayJC. Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nat Genet2008; 40:1341–7.
12.
HiguchiR. Simple and rapid preparation of samples for PCR. In PCR technology. Stocton Press. New York, 1989; 31–38.
13.
de BakkerPIYelenskyRPe'erIGabrielSBDalyMJAltshulerD. Efficiency and power in genetic association studies. Nat Genet2005; 37:1217–23.
14.
BarrettJCFryBMailerJDalyMJ. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics2005; 21:263–5.
15.
HorvathSXuXLairdNM. The family based association test method: Strategies for studying general genotype-phenotype associations. Eur J Hum Genet2001; 9:301–6.
16.
HorvathSXuXLakeSLSilvermanEKWeissSTLairdNM. Family-based tests for associating haplotypes with general phenotype data: Application to asthma genetics. Genet Epidemiol2004; 26:61–9.
17.
JugessurAMurrayJC. Orofacial clefting: Recent insights into a complex trait. Curr Opin Genet Dev2005; 15:270–8.
18.
MangoldELudwigKUBirnbaumSBaluardoCFerrianMHermsSReutterHde AssisNAChawaTAMattheisenMSteffensMBarthSKluckNPaulABeckerJLausterCSchmidtGBraumannBScheerMReichRHHemprichAPotzschSBlaumeiserBMoebusSKrawczakMSchreiberSMeitingerTWichmannHESteegers-TheunissenRPKramerFJCichonSProppingPWienkerTFKnappMRubiniMMosseyPAHoffmannPNothenMM. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet2010; 42:24–6.
19.
BeatyTHMurrayJCMarazitaMLMungerRGRuczinskiIHetmanskiJBLiangKYWuTMurrayTFallinMDRedettRARaymondGSchwenderHJinSCCooperMEDunnwaldMMansillaMALeslieEBullardSLidralACMorenoLMMenezesRVieiraARPetrinAWilcoxAJLieRTJabsEWWu-ChouYHChenPKWangHYeXHuangSYeowVChongSSJeeSHShiBChristensenKMelbyeMDohenyKFPughEWLingHCastillaEECzeizelAEMaLFieldLLBrodyLPangilinanFMillsJLMolloyAMKirkePNScottJMArcos-BurgosMScottAF. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet2010; 42:525–9.
20.
ScapoliLMartinelliMPezzettiFPalmieriAGirardiASavoiaABiancoAMCarinciF. Expression and association data strongly support JARID2 involvement in nonsyndromic cleft lip with or without cleft palate. Hum Mutat2010; 31:794–800.
