The aims of this review are (1) to illustrate current knowledge of the mode of inheritance and the loci involved in the cleft lip and palate and (2) to summarize the results of our investigations, which were carried out in Italy. It is well established that nonsyndromic cleft of the lip with or without the palate (CL±P) and cleft palate only (CPO) are separate entities. Genetic heterogeneity has been observed in CL±P, which involves different chromosome regions, mainly 6p23 (OFC1), 2q13 (OFC2), and 19q13.2 (OFC3), as well as other loci, such as 4q25-4q31.3 and 17q21. Furthermore, an interaction between different genes has been suggested in the oligogenic model. In one case at least, an OFC1 and OFC2 interaction has been demonstrated.
The mode of inheritance of CPO is compatible with a recessive single major gene model, while an association with a candidate gene, mapping on the chromosome region 2q13/TGF α, remains to be confirmed.
AmosC.GasserD.HechtJ.T.. Nonsyndromic cleft lip with or without cleft palate: new BCL3 information.Am J Hum Genetics.1996a; 59: 743–744.
2.
AmosC.SteinJ.MullikenJ.B.StalS.MalcomS.WinterR.BlantonS.H.SeemanovaE.GasserD.L.HechtJ.T.. Nonsyndromic cleft lip with or without cleft palate: erratum.Am J Hum Genetics.1996b; 59: 744.
3.
ArdingerH.H.BuetowK.H.BellG.I.BardachJ.Van DemarkD.R.MurrayJ.C.. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate.Am J Hum Genetics.1989; 45: 348–353.
4.
AsadaH.KawamuraY.MaruyamaK.KumeH.DingR.G.KanbaraN.KuzumeH.SanboM.YagiT.ObataK.. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase.Proc Natl Acad Sci USA.1997; 94: 6496–6499.
5.
BeiraghiS.ForoudT.DloutyS.BixlerD.Delohter-BlanchetD.ConneallyP.M.HodesM.E.. Possible localization of a major gene for cleft lip and palate to 4q.Clin Genetics.1994; 46: 255–256.
6.
BlantonS.H.CrowderE.MalcomS.WinterR.GasserD.L.StalS.MullikenJ.HechtJ.T.. Exclusion of linkage between cleft lip with or without cleft palate and marker on chromosome 4 and 6.Am J Hum Genetics.1996; 58: 239–241.
7.
Bonaiti-PellieC.BriandM.L.FeingoldJ.PavyB.PsaumeJ.Migne-TufferG.KaplanJ.. An epidemiological and genetic study of facial clefting in France. I. Epidemiological and frequency in relatives.J Med Genetics.1982; 11: 374–377.
8.
CarinciF.PezzettiF.ScapoliL.PadulaE.BacilieroU.CurioniC.TognonM.. Nonsyndromic cleft lip and palate: evidence of linkage to microsatellite markers on 6p23.Am J Hum Genetics.1995; 56: 337–339.
9.
CarterC.O.. Genetics of common single malformations.Br Med Bull.1976; 32: 21–26.
10.
Chenevix-TrenchG.JonesK.GreenA.C.DuffyD.L.MartinN.G.. Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci.Am J Hum Genetics.1992; 51: 1377–1385.
11.
Chenevix-TrenchG.JonesK.GreenA.C.MartinN.. Further evidence for an association between genetic variation in transforming growth factor alpha and cleft lip and palate.Am J Hum Genetics.1991; 48: 1012–1013.
12.
ChristensenK.Fogh-AndersenP.. Etiological sub-groups in nonsyndromic isolated cleft palate. A genetic-epidemiological study of 52 Danish birth cohorts.Clin Genetics.1994; 46: 329–335.
ChungC.S.BixlerD.WatanabeT.KoguchiH.Fogh-AndersenP.. Segregation analysis of cleft lip with or without cleft palate: a comparison of Danish and Japanese data.Am J Hum Genetics.1986; 39: 603–611.
15.
ClementiM.TenconiR.CollinsA.CalzolariE.MilanM.. Complex segregation analysis in a sample of consecutive newborns with cleft lip with or without cleft palate in Italy.Hum Hered.1995; 45: 157–164.
16.
ClementiM.TenconiR.ForaboscoP.. Inheritance of cleft palate in Italy. Evidence for a major autosomal recessive locus.Hum Genetics.1997; 100: 204–209.
17.
ClouthierD.E.HosodaK.RichardsonJ.A.WilliamsS.C.YanagisawaH.KuwakiT.KumadaM.HammerR.E.YanagisawaM.. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice.Development.1998; 125(5): 813–824.
18.
DaviesA.F.StephensR.J.OlavesenM.G.HeatherL.DixonM.J.MageeA.FlinterF.RagoussisJ.. Evidence of a locus for orofacial clefting on human chromosome 6p24 and STS content map of the region.Hum Mol Genetics.1995; 4: 121–128.
19.
De PaepeA.. Dominantly inherited cleft lip and palate.J Med Genetics.1989; 26: 794.
20.
DiehlS.R.EricksonR.P.. Genome scan for teratogen-induced clefting susceptibility loci in the mouse: evidence of both allelic and locus heterogeneity distinguishing cleft lip and cleft palate.Proc Natl Acad Sci USA.1997; 94: 5231–5236.
21.
DonnaiD.HeatherL.J.SinclairP.ThakkerY.ScamblerP.DixonM.J.. Association of autosomal dominant cleft lip palate and translocation 6p23;9q22.3.Clin Dysmorph.1992; 1: 89–97.
22.
EibergH.BixlerD.NielsenL.S.ConneallyP.M.MohrJ.. Suggestion of linkage of a major locus for nonsyndromic orofacial cleft with F13A and tentative assignment to chromosome 6.Clin Genetics.1987; 32: 129–132.
23.
FarrallM.BuetowK.H.MurrayJ.C.. Resolving an apparent paradox concerning the role of TGFA in CL/P.Am J Hum Genetics.1993; 52: 434–436.
24.
FarrallM.HolderS.. Familial recurrence-pattern analysis of cleft lip with or without cleft palate.Am J Hum Genetics.1992; 50: 270–277.
25.
FengH.SassaniR.BartlettS.P.LeeA.HechtJ.T.MalcomS.WinterR.M.VintinerG.M.BuetowK.H.GasserD.L.. Evidence from family studies, for linkage disequilibrium between TGFA and a gene for nonsyndromic cleft lip with or without cleft palate.Am J Hum Genetics.1994; 55: 932–936.
FieldL.L.RayA.K.MarazitaM.L.. Transforming growth factor alpha: a modifying locus for nonsyndromic cleft lip with or without cleft palate?Eur J Hum Genetics.1994; 2: 159–165.
28.
FitzpatrickD.FarralM.. An estimation of the number of susceptibility loci for isolated cleft palate.J Craniofac Genet Dev Biol.1993; 13: 230–235.
29.
Fogh-AndersenP.. Inheritance of Harelip and Cleft Palate.Copenhagen: Busck;1942.
30.
ForbesS.A.BrennanL.RichardsonM.CoffeyA.ColeC.G.GregoryS.G.BentleyD.R.MummS.MooreG.E.StainerP.. Refined mapping and YAC contig construction of the X-linked cleft palate and ankyloglossia locus including the proximal X-Y homology breakpoint within Xq21.3.Genomics.1996; 31: 36–43.
31.
FraserF.C.. The genetics of cleft lip and palate.Am J Hum Genetics.1970; 22: 336–352.
32.
HansonJ.W.. Risk of the offspring of women treated with hydantoin anticonvulsant with emphasis on the fetal hydantoin syndrome.J Pediatr.1989; 4: 662–668.
33.
HechtJ.T.WangY.BlantonS.H.MichelsV.V.DaigerS.P.. Cleft lip and palate: no evidence of linkage to transforming growth factor alpha.Am J Hum Genetics.1991a; 49: 682–686.
34.
HechtJ.T.WangY.ConnorB.BlantonS.H.DaigerS.P.. Nonsyndromic cleft lip and palate: no evidence of linkage to HLA or factor 13A.Am J Hum Genetics.1993; 52: 1230–1233.
35.
HechtJ.T.YangP.MichelsV.V.BuetowK.H.. Complex segregation analysis of nonsyndromic cleft lip and palate.Am J Hum Genetics.1991b; 49: 674–681.
36.
HolderS.E.VintinerG.M.FarrenB.MalcolmS.WinterR.M.. Confirmation of an association between RFLPs at the transforming growth factor-alpha locus and nonsyndromic cleft lip and palate.J Med Genetics.1992; 29: 390–392.
37.
HomanicsG.E.DeLoreyT.M.FirestoneL.L.QuinlanJ.J.HandforthA.HarrisonN.L.KrasowskiM.D.RickC.E.KorpiE.R.MakelaR.BrilliantM.H.HagiwaraN.FergusonC.SnyderK.OlsenR.W.. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior.Proc Natl Acad Sci USA.1997; 94: 4143–4148.
38.
HwangS.J.BeatyT.H.PannyS.R.StreetN.A.JosephJ.M.GordonS.McIntoshI.FrancomanoC.A.. Association study of transforming growth factor alpha Taq I polymorphism and oral cleft: indication of gene-environment interaction in a population-based sample of infant with birth defect.Am J Epidemiol.1995; 141: 629–636.
39.
JaraL.BlancoR.ChiffelleI.PalominoH.CarrenoH.. Associations between alleles of the transforming growth factor alpha locus and cleft lip and palate in the Chilean population.Am J Med Genetics.1995; 57: 548–551.
40.
KaartinenV.VonckenJ.W.ShulerC.WarburtonD.BuD.HeisterkampN.GroffenJ.. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction.Nat Genetics.1995; 11: 415–421.
41.
Korman-BortolottoM.H.FarahL.M.S.SoaresD.CorbaniM.MüllerR.AdellA.C.A.. Terminal deletion 6p23: a case report.Am J Med Genetics.1990; 37: 475–477.
42.
KuriharaY.KuriharaH.SuzukiH.KodamaT.MaemuraK.NagaiR.OdaH.KuwakiT.CaoW.H.KamadaN.JishageK.OuchiY.AzumaS.ToyodaY.IshikawaT.KumadaM.YazakiY.. Elevated pressure and craniofacial abnormalities in mice deficient in endothelin-1.Nature.1994; 368: 703–710.
43.
LidralA.C.MurrayJ.C.BuetowK.H.BasartA.M.SchearerH.ShiangR.NavalA.LaydaE.MageeK.MageeW.. 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.
44.
LidralA.C.RomittiP.A.BasartA.M.DoetschmanT.LeysensN.J.Daack-HirschS.SeminaE.V.JohnsonL.R.MachidaJ.BurdsA.ParnellT.J.RubensteinJ.L.MurrayJ.C.. Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.Am J Hum Genetics.1998; 63: 557–568.
45.
MaestriN.E.BeatyT.H.HetmanskiJ.SmithE.A.McIntoshI.WyszynskiD.F.LiangK.Y.DuffyD.L.VanderKolkC.. Application of transmission disequilibrium tests to nonsyndromic oral clefts: including candidate genes and environmental exposures in the models.Am J Med Genetics.1997; 73: 337–344.
46.
MarazitaM.L.HuD.N.SpenceA.LiuY.E.MelnickM.. Cleft lip with or without cleft palate in Shanghai, China: evidence for an autosomal major locus.Am J Hum Genetics.1992; 51: 648–653.
47.
MarazitaM.L.SpenceM.A.MelnickM.. Genetic analysis of cleft lip with or without cleft palate in Danish kindreds.Am J Med Genetics.1984; 19: 9–18.
48.
MarazitaM.L.SpenceM.A.MelnickM.. Major gene determination of liability to cleft lip with or without cleft palate: a multiracial view.J Craniofac Genet Dev Biol.1986; 2(Suppl.): 89–97.
49.
MartinelliM.ScapoliL.PezzettiF.CarinciF.CarinciP.BacilieroU.PadulaE.TognonM.. Suggestive linkage between markers on chromosome 19q13.2 and nonsyndromic orofacial cleft malformation.Genomics.1998; 51: 177–181.
50.
MehraS.VermaI.C.. Ecogenetics of congenital craniofacial malformation. International Committee on The Human Genome.Am J Hum Genetics.1991; 49(Suppl.): A150.
51.
MelnickM.BixlerD.Fogh-Anderson P ConneallyP.M.. Cleft ± cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968.Am J Med Genetics.1980; 6: 83–97.
52.
MilanM.AstolfiG.VolpatoS.GaraniG.P.ClementiM.TenconiR.BoniS.CalzolariE.. 766 case of oral cleft in Italy. Data from Emilia-Romagna (IMER) and Northeast Italy (NEI) register.Eur J Epidemiol.1994; 10: 317–324.
53.
MitchellL.E.. Interpreting the evidence for an association between the retinoic acid receptor locus and nonsyndromic cleft lip with or without cleft palate.J Med Genetics.1994; 31: 425.
54.
MitchellL.E.. Transforming growth factor alpha locus and nonsyndromic cleft lip with or without cleft palate: a reappraisal.Genet Epidemiol.1997; 14: 231–240.
55.
MitchellL.E.HealeyS.C., 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 Genetics.1995; 57: 1130–1136.
56.
MitchellL.E.RischN.. Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis.Am J Hum Genetics.1992; 51: 323–332.
57.
MurrayJ.C.. Face facts: genes, environment, and cleft.Am J Hum Genetics.1995; 57: 227–232.
58.
OttJ.. Analysis of Human Genetic Linkage.Baltimore: The Johns Hopkins Press;1991.
59.
Pezzetti F ScapoliL.MartinelliM.Carinci F BodoM.Carinci P TognonM.. A locus in 2p13-14, in addition to that mapped in 6p23, is involved in nonsyndromic familial orofacial cleft malformation.Genomics.1998; 50: 299–305.
60.
PierpontJ.W.StormA.L.EricksonR.P.KohnB.R.PettijohnL.DePaepeA.. Lack of linkage of apparently dominant cleft lip (palate) to two candidate chromosomal region.J Craniofac Genet Dev Biol.1995; 15: 66–71.
61.
RayA.K.FieldL.L.MarazitaM.L.. Nonsyndromic cleft lip with or without cleft palate in West Bengal, India: evidence for an autosomal major locus.Am J Hum Genetics.1993; 52: 1006–1011.
62.
SassaniR.BartletS.P.FengH.Goldner-SauveA.HaqA.K.BuetowK.H.GasserD.L.. Associations between alleles of the transforming growth factor-alpha locus and the occurrence of cleft lip.Am J Med Genetics.1993; 45: 565–569.
63.
SatokataI.MaasR.. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development.Nat Genetics.1994; 6: 348–356.
64.
ScapoliL.PezzettiF.CarinciF.MartinelliM.CarinciP.TognonM.. Genetic heterogeneity and evidence of linkage to 6p23 in nonsyndromic cleft lip with or without cleft palate.Genomics.1997; 43: 216–220.
65.
ScapoliL.PezzettiF.CarinciF.MartinelliM.CarinciP.TognonM.. Lack of linkage disequilibrium between transforming growth factor alpha Taq I polymorphism and cleft lip with or without cleft palate in families from northeastern Italy.Am JMed Genetics.1998; 75: 203–206.
66.
ShawD.RayA.MarazitaM.FieldL.. Further evidence of a relationship between the retinoic acid receptor alpha locus and nonsyndromic cleft lip with or without cleft palate CL±P.Am J Hum Genetics.1993; 53: 1156–1157.
ShiangR.LidralA.C.ArdingerH.H.BuetowK.H.RomittiP.A.MungerR.G.MurrayJ.C.. Association of transforming alpha 4 gene polymorphism with nonsyndromic cleft palate only CPO.Am J Hum Genetics.1993; 53: 836–843.
69.
ShieldsE.D.BixlerD.Fogh-AndersenP.. Cleft palate: a genetic and epidemiologic investigation.Clin Genetics.1981; 20: 13–24.
70.
SpielmanR.S.McGinnisR.E.EwensW.J.. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).Am J Hum Genetics.1993; 52: 506–516.
71.
SteinJ.Hecht JT BlantonS.H.. Exclusion of retinoic acid receptor and a cartilage matrix protein in nonsyndromic CL(P) families.J Med Genetics.1995a; 32: 78.
72.
SteinJ.MullikenJ.B.StalS.GasserD.L.MalcolmS.WinterR.BlantonS.H.AmosC.SeemanovaE.HechtJ.T.. Nonsyndromic cleft lip with or without cleft palate: evidence of linkage to BCL3 in 17 multigenerational families.Am J Hum Genetics.1995b; 57: 257–272.
73.
StollC.QuianJ.F.FeringoldJ.Sauvage P MayE.. Genetic variation in transforming growth factor alpha: possible association of Bam HI polymorphism with bilateral sporadic cleft lip and palate.Am J Hum Genetics.1992; 50: 870–871.
74.
StollC.Quian JF FeringoldJ.Sauvage P MayE.. Genetic variation in transforming growth factor alpha: possible association of Bam HI polymorphism with bilateral sporadic cleft lip and palate.Hum Genetics.1993; 92: 81–82.
75.
TempleK.CalvertM.PlintD.ThompsonE.PembreyM.. Dominantly inherited cleft lip and palate in two families.J Med Genetics.1989; 26: 386–389.
76.
ThomasT.KuriharaH.YamagishiH.KuriharaY.YazakiY.OlsonE.N.SrivastavaD.. A signaling cascade involving endothelin-1, dHAND and MSX1 regulates development of neural-crest–derived branchial arch mesenchyme.Development.1998; 125: 3005–3014.
77.
Van DykeD.C.GoldmanA.S.SpielmanR.S.ZmijewskiC.M.OkaS.W.. Segregation of HLA in sibs with cleft lip or cleft lip and palate: evidence against linkage.Cleft Palate J.1980; 17: 189–193.
78.
VintinerG.M.HolderS.E.WinterR.M.MalcolmS.. No evidence of linkage between the transforming growth factor alpha gene in families with apparently autosomal dominant inheritance of cleft lip and palate.J Med Genetics.1992; 29: 393–397.
79.
VintinerG.M.LoK.K.HolderS.E.MinterR.M.MalcolmS.. Exclusion of candidate genes from a role in cleft lip with or without cleft palate: linkage and association studies.J Med Genetics.1993; 30: 773–778.
80.
WatanabeT.OhishiM.TashiroH.. Population and family studies of HLA in Japanese with cleft lip and palate.Cleft Palate J.1984; 21: 293–300.
81.
WeeksD.E.LangeK.. The affected-pedigree-member method of linkage analysis.Am J Hum Genetics.1988; 42: 315–326.
82.
WoolfC.M.WolfR.M.BroadbentT.R.. A genetic study of cleft lip and palate in Utah.Am J Hum Genetics.1963; 15: 209–215.
WyszynskiD.F.MaestriN.LewandaA.F.McIntoshI.SmithE.A.Garcia-DelgadoC.Vinageras-GuarnerosE.WulfsbergE.BeatyT.H.. 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 Genetics.1997a; 9: 101–109.
85.
WyszynskiD.F.MaestriN.McIntoshI.SmithE.A.LewandaA.F.Garcia-DelgadoC.Vinageras-GuarnerosE.WulfsbergE.BeatyT.H.. Evidence for an association between markers on chromosome 19q and non-syndromic cleft lip with or without cleft palate in two groups of multiplex families.Hum Genetics.1997b; 9: 22–26.
86.
YanagisawaH.YanagisawaM.KapurR.P.RichardsonJ.A.WilliamsS.C.ClouthierD.E.de WitD.EmotoN.HammerR.E.. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene.Development.1998; 125(5): 825–836.
