Details of Disease

Disease Name

Isolated cleft lip

isolated cleft lip (disease); nonsyndromic cleft lip (disease)

Definition

Isolated cleft lip is a fissure type embryopathy extending from the upper lip to the nasal base.

Disease Hierarchy

DISQCXZX: Disorder of development or morphogenesis

DISV3XW6: Cleft lip

DIS2O2JV: Isolated cleft lip

Disease Identifiers

MONDO ID

MONDO_0016043

MESH ID

D002971

UMLS CUI

C0008924

MedGen ID

40327

HPO ID

HP:0000204

Orphanet ID

199302

SNOMED CT ID

80281008

General Information of Disease (ID: DIS2O2JV)

Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 35 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
BMP4	TTD3BSX	Limited	Genetic Variation	[1]
FGFR1	TTRLW2X	Limited	Genetic Variation	[2]
TGFB3	TTWOMY8	Limited	Biomarker	[3]
FBXO11	TT6G10V	moderate	Biomarker	[4]
CDH1	TTLAWO6	Strong	Genetic Variation	[5]
CLK3	TTQPE1U	Strong	Genetic Variation	[2]
EPHA3	TTHS2LR	Strong	Genetic Variation	[6]
EPHB3	TT5LM7U	Strong	Biomarker	[7]
ESRRG	TT9ZRHB	Strong	Genetic Variation	[8]
F13A1	TTXI2RA	Strong	Biomarker	[9]
FGF10	TTNPEFX	Strong	Biomarker	[10]
FGF18	TT6ICRA	Strong	Biomarker	[10]
FGF2	TTGKIED	Strong	Biomarker	[11]
FGF7	TTFY134	Strong	Biomarker	[10]
FGF8	TTIUF3J	Strong	Biomarker	[11]
FGFR2	TTGJVQM	Strong	Biomarker	[12]
FGFR3	TTST7KB	Strong	Biomarker	[11]
HHAT	TT1VNCG	Strong	Genetic Variation	[13]
MKNK2	TTRECN3	Strong	Genetic Variation	[14]
MTHFR	TTQWOU1	Strong	Genetic Variation	[15]
MTR	TTUTO39	Strong	Biomarker	[16]
MYC	TTNQ5ZP	Strong	Biomarker	[17]
NEK2	TT3VZ24	Strong	Biomarker	[18]
NOS3	TTCM4B3	Strong	Biomarker	[16]
NR1D1	TTAD1O8	Strong	Biomarker	[19]
NRG1	TTEH395	Strong	Genetic Variation	[20]
NTN1	TT0AH4L	Strong	Biomarker	[21]
PDGFC	TTOABM9	Strong	Genetic Variation	[22]
PHF8	TT81PFE	Strong	Altered Expression	[23]
PLEKHA5	TTCDZMO	Strong	Biomarker	[24]
SEMA4D	TT5UT28	Strong	Genetic Variation	[14]
SLC19A1	TT09I7D	Strong	Biomarker	[16]
TFAP2A	TTDY4BS	Strong	CausalMutation	[25]
TGFA	TTTLQFR	Strong	Genetic Variation	[26]
TYMS	TTP1UKZ	Strong	Genetic Variation	[27]
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⏷ Show the Full List of 35 DTT(s)

This Disease Is Related to 2 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC25A21	DT2UQYR	Strong	Genetic Variation	[2]
SLC31A1	DTP8L4F	Strong	Genetic Variation	[28]
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This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
FPGS	DECWT2V	Strong	Biomarker	[29]
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This Disease Is Related to 57 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
CRNKL1	OTWBQNGU	moderate	Biomarker	[30]
ESRP2	OTVTKJ4I	moderate	Biomarker	[24]
FOXE1	OT5IR5IT	moderate	Genetic Variation	[31]
PLEKHA7	OTNUMAZ0	moderate	Biomarker	[24]
PTCH1	OTMG07H5	moderate	Genetic Variation	[32]
ADTRP	OTFI2BQX	Strong	Genetic Variation	[33]
ARHGAP29	OT8JH4TY	Strong	Genetic Variation	[6]
ARID3B	OTUP9MS4	Strong	Genetic Variation	[20]
BARX1	OT2VP73H	Strong	Altered Expression	[34]
BHMT2	OTWYGLDU	Strong	Biomarker	[16]
CMSS1	OTHASLWD	Strong	Genetic Variation	[2]
COL21A1	OT7GS82E	Strong	Genetic Variation	[35]
COL8A1	OTWBTED2	Strong	Genetic Variation	[2]
CRISPLD2	OTVSFHTL	Strong	Genetic Variation	[36]
CYRIA	OT2VJ767	Strong	Genetic Variation	[2]
DEPDC5	OTE70JLY	Strong	Genetic Variation	[2]
FGF3	OT9PK2SI	Strong	Biomarker	[10]
FGF9	OT2SKDGM	Strong	Biomarker	[11]
FILIP1L	OTPY8IMS	Strong	Genetic Variation	[2]
GABRB3	OT80C3D4	Strong	Genetic Variation	[37]
GADD45G	OT8V1J4M	Strong	Genetic Variation	[38]
GNB1L	OTXSUD8R	Strong	Genetic Variation	[2]
GOSR2	OTYHIYN2	Strong	Genetic Variation	[2]
JAM3	OTX0F9QL	Strong	Genetic Variation	[39]
MSX1	OT5U41ZP	Strong	Biomarker	[3]
MTHFS	OTZ39JNR	Strong	Biomarker	[16]
MTMR3	OTBIT23O	Strong	Genetic Variation	[2]
MYH14	OT1TZEJK	Strong	Biomarker	[40]
NAA25	OTS3QVF1	Strong	Genetic Variation	[2]
NECTIN1	OTTE5ZR6	Strong	Genetic Variation	[41]
PAX7	OTDMQRPO	Strong	Genetic Variation	[2]
PAX9	OT25J0F7	Strong	Genetic Variation	[42]
RAD54B	OTMWB2P2	Strong	Genetic Variation	[2]
RPL5	OTM8EBRI	Strong	Genetic Variation	[43]
RPS26	OTBYTA6A	Strong	Genetic Variation	[2]
RYK	OTZ3WWZH	Strong	Genetic Variation	[7]
SALL4	OTC08PR5	Strong	Genetic Variation	[2]
SFI1	OTI1P52G	Strong	Genetic Variation	[2]
SH3BP4	OTVIRKW7	Strong	Genetic Variation	[44]
SHROOM3	OTQKC5X2	Strong	Genetic Variation	[20]
SHTN1	OTB07MOG	Strong	Genetic Variation	[45]
SMC1A	OT9ZMRK9	Strong	Genetic Variation	[46]
SPRY2	OTH0CRCZ	Strong	Biomarker	[47]
STK3	OTLNSCQD	Strong	Genetic Variation	[2]
SUMO1	OTJFD4P5	Strong	Genetic Variation	[48]
SYT14	OTE1V1OW	Strong	Genetic Variation	[6]
TACC1	OTGX20TE	Strong	Genetic Variation	[18]
TBCA	OTCCWMGK	Strong	Genetic Variation	[49]
TBX22	OTT1RM26	Strong	Biomarker	[50]
TCN2	OT41D0L3	Strong	Biomarker	[51]
THADA	OTYZQX0F	Strong	Genetic Variation	[6]
TMCO4	OTFPK182	Strong	Genetic Variation	[2]
TMEM19	OTKWMDYH	Strong	Genetic Variation	[2]
TOX3	OTC9NR4W	Strong	Genetic Variation	[35]
TP63	OT0WOOKQ	Strong	Genetic Variation	[20]
TRAF3IP3	OTNG0L8X	Strong	Genetic Variation	[6]
TTF2	OT5LJOWM	Strong	Genetic Variation	[52]
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⏷ Show the Full List of 57 DOT(s)

References

1	Association between BMP4 gene polymorphisms and cleft lip with or without cleft palate in a population from South China.Arch Oral Biol. 2018 Sep;93:95-99. doi: 10.1016/j.archoralbio.2018.05.015. Epub 2018 May 22.
2	Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.Nat Commun. 2017 Feb 24;8:14364. doi: 10.1038/ncomms14364.
3	TGF3, MSX1, and MMP3 as Candidates for NSCLP in an Indian Population.Cleft Palate Craniofac J. 2019 Mar;56(3):363-372. doi: 10.1177/1055665618775727. Epub 2018 May 8.
4	A mutation in the F-box gene, Fbxo11, causes otitis media in the Jeff mouse.Hum Mol Genet. 2006 Nov 15;15(22):3273-9. doi: 10.1093/hmg/ddl403. Epub 2006 Oct 11.
5	Association between CDH1 and MSX1 gene polymorphisms and the risk of nonsyndromic cleft lip and/or cleft palate in a southeast Iranian population.Cleft Palate Craniofac J. 2013 Sep;50(5):e98-e104. doi: 10.1597/12-144. Epub 2012 Dec 11.
6	Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci.Nat Genet. 2012 Sep;44(9):968-71. doi: 10.1038/ng.2360. Epub 2012 Aug 5.
7	A mutation in RYK is a genetic factor for nonsyndromic cleft lip and palate.Cleft Palate Craniofac J. 2006 May;43(3):310-6. doi: 10.1597/04-145.1.
8	A Genome-Wide Search for Gene-Environment Effects in Isolated Cleft Lip with or without Cleft Palate Triads Points to an Interaction between Maternal Periconceptional Vitamin Use and Variants in ESRRG.Front Genet. 2018 Feb 26;9:60. doi: 10.3389/fgene.2018.00060. eCollection 2018.
9	Is there a genetic relationship between epilepsy and birth defects?.Neurology. 1992 Apr;42(4 Suppl 5):63-7.
10	Impaired FGF signaling contributes to cleft lip and palate. Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4512-7. doi: 10.1073/pnas.0607956104. Epub 2007 Mar 6.
11	Sequence evaluation of FGF and FGFR gene conserved non-coding elements in non-syndromic cleft lip and palate cases.Am J Med Genet A. 2007 Dec 15;143A(24):3228-34. doi: 10.1002/ajmg.a.31965.
12	Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing.Birth Defects Res. 2017 Jul 17;109(13):1030-1038. doi: 10.1002/bdr2.23605.
13	Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis.J Clin Invest. 2014 Apr;124(4):1660-71. doi: 10.1172/JCI72688. Epub 2014 Mar 3.
14	Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip cleft palate and cleft palate only.Hum Mol Genet. 2017 Feb 15;26(4):829-842. doi: 10.1093/hmg/ddx012.
15	LINE-1 methylation in cleft lip tissues: Influence of infant MTHFR c.677C>T genotype.Oral Dis. 2019 Sep;25(6):1668-1671. doi: 10.1111/odi.13136. Epub 2019 Jun 20.
16	Folate pathway and nonsyndromic cleft lip and palate.Birth Defects Res A Clin Mol Teratol. 2011 Jan;91(1):50-60. doi: 10.1002/bdra.20740. Epub 2010 Dec 1.
17	Long-range enhancers regulating Myc expression are required for normal facial morphogenesis.Nat Genet. 2014 Jul;46(7):753-8. doi: 10.1038/ng.2971. Epub 2014 May 25.
18	Molecular contribution to cleft palate production in cleft lip mice.Congenit Anom (Kyoto). 2014 May;54(2):94-9. doi: 10.1111/cga.12038.
19	Application of transmission disequilibrium tests to nonsyndromic oral clefts: including candidate genes and environmental exposures in the models.Am J Med Genet. 1997 Dec 19;73(3):337-44. doi: 10.1002/(sici)1096-8628(19971219)73:3<337::aid-ajmg21>3.0.co;2-j.
20	Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate.Hum Genet. 2017 Mar;136(3):275-286. doi: 10.1007/s00439-016-1754-7. Epub 2017 Jan 4.
21	NTN1 gene was risk to non-syndromic cleft lip only among Han Chinese population.Oral Dis. 2019 Mar;25(2):535-542. doi: 10.1111/odi.13009. Epub 2018 Dec 19.
22	Maternal transmission effect of a PDGF-C SNP on nonsyndromic cleft lip with or without palate from a Chinese population.PLoS One. 2012;7(9):e46477. doi: 10.1371/journal.pone.0046477. Epub 2012 Sep 28.
23	PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase.Hum Mol Genet. 2010 Jan 15;19(2):217-22. doi: 10.1093/hmg/ddp480. Epub 2009 Oct 19.
24	Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.Am J Hum Genet. 2018 Jun 7;102(6):1143-1157. doi: 10.1016/j.ajhg.2018.04.009. Epub 2018 May 24.
25	A clinical and molecular analysis of branchio-oculo-facial syndrome patients in Russia revealed new mutations in TFAP2A.Ann Hum Genet. 2015 Mar;79(2):148-52. doi: 10.1111/ahg.12098. Epub 2015 Jan 15.
26	Transforming Growth Factor Alpha Taq I Polymorphisms and Nonsyndromic Cleft Lip and/or Palate Risk: A Meta-Analysis.Cleft Palate Craniofac J. 2018 Jul;55(6):814-820. doi: 10.1597/16-008. Epub 2018 Feb 22.
27	Thymidylate synthase polymorphisms and risks of human orofacial clefts.Birth Defects Res A Clin Mol Teratol. 2013 Feb;97(2):95-100. doi: 10.1002/bdra.23114.
28	Searching for genes for cleft lip and/or palate based on breakpoint analysis of a balanced translocation t(9;17)(q32;q12).Cleft Palate Craniofac J. 2009 Sep;46(5):532-40. doi: 10.1597/08-047.1. Epub 2009 Feb 2.
29	FPGS gene is a novel causative gene for cleft lip in China.Med Hypotheses. 2011 Mar;76(3):371-3. doi: 10.1016/j.mehy.2010.10.043. Epub 2010 Nov 19.
30	Wnt9b is the mutated gene involved in multifactorial nonsyndromic cleft lip with or without cleft palate in A/WySn mice, as confirmed by a genetic complementation test.Birth Defects Res A Clin Mol Teratol. 2006 Aug;76(8):574-9. doi: 10.1002/bdra.20302.
31	FOXE1 polymorphisms and non-syndromic orofacial cleft susceptibility in a Chinese Han population.Oral Dis. 2016 May;22(4):274-9. doi: 10.1111/odi.12435. Epub 2016 Jan 20.
32	A novel PTCH1 mutation underlies nonsyndromic cleft lip and/or palate in a Han Chinese family.Oral Dis. 2018 Oct;24(7):1318-1325. doi: 10.1111/odi.12915. Epub 2018 Jul 9.
33	Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate.Genet Epidemiol. 2011 Sep;35(6):469-78. doi: 10.1002/gepi.20595. Epub 2011 May 26.
34	Barx1, growth factors and apoptosis in facial tissue of children with clefts.Stomatologija. 2008;10(2):62-6.
35	Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and/or palate.Mol Genet Genomic Med. 2019 May;7(5):e635. doi: 10.1002/mgg3.635. Epub 2019 Mar 28.
36	Association Between CRISPLD2 Polymorphisms and the Risk of Nonsyndromic Clefts of the Lip and/or Palate: A Meta-analysis.Cleft Palate Craniofac J. 2018 Mar;55(3):328-334. doi: 10.1177/1055665617738995. Epub 2017 Dec 14.
37	Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate.Hum Genet. 2002 Jan;110(1):15-20. doi: 10.1007/s00439-001-0639-5. Epub 2001 Nov 10.
38	Mutations of GADD45G in rabbits cause cleft lip by the disorder of proliferation, apoptosis and epithelial-mesenchymal transition (EMT).Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2356-2367. doi: 10.1016/j.bbadis.2019.05.015. Epub 2019 May 29.
39	A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4.Nat Genet. 2010 Jun;42(6):525-9. doi: 10.1038/ng.580. Epub 2010 May 2.
40	Investigation of MYH14 as a candidate gene in cleft lip with or without cleft palate.Eur J Oral Sci. 2008 Jun;116(3):287-90. doi: 10.1111/j.1600-0722.2008.00534.x.
41	Novel insertion mutation in the PVRL1 gene in Turkish patients with non-syndromic cleft lip with/without cleft palate.Arch Oral Biol. 2014 Mar;59(3):237-40. doi: 10.1016/j.archoralbio.2013.11.016. Epub 2013 Dec 7.
42	SNPs and interaction analyses of IRF6, MSX1 and PAX9 genes in patients with nonsyndromic cleft lip with or without palate.Mol Med Rep. 2013 Oct;8(4):1228-34. doi: 10.3892/mmr.2013.1617. Epub 2013 Aug 6.
43	Molecular pathogenesis in Diamond-Blackfan anemia.Int J Hematol. 2010 Oct;92(3):413-8. doi: 10.1007/s12185-010-0693-7. Epub 2010 Sep 30.
44	Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts.Am J Med Genet A. 2012 Apr;158A(4):784-94. doi: 10.1002/ajmg.a.35257. Epub 2012 Mar 14.
45	Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology.PLoS Genet. 2018 Aug 1;14(8):e1007501. doi: 10.1371/journal.pgen.1007501. eCollection 2018 Aug.
46	Novel findings of left ventricular non-compaction cardiomyopathy, microform cleft lip and poor vision in patient with SMC1A-associated Cornelia de Lange syndrome.Am J Med Genet A. 2017 Feb;173(2):414-420. doi: 10.1002/ajmg.a.38030. Epub 2016 Nov 7.
47	Stage-dependent craniofacial defects resulting from Sprouty2 overexpression.Dev Dyn. 2007 Jul;236(7):1918-28. doi: 10.1002/dvdy.21195.
48	SUMO1 genetic polymorphisms may contribute to the risk of nonsyndromic cleft lip with or without palate: a meta-analysis.Genet Test Mol Biomarkers. 2014 Sep;18(9):616-24. doi: 10.1089/gtmb.2014.0056. Epub 2014 Aug 11.
49	Psychosocial Adjustments Among Adolescents With Craniofacial Conditions and the Influence of Social Factors: A Multi-Informant Study.Cleft Palate Craniofac J. 2020 May;57(5):624-636. doi: 10.1177/1055665619888308. Epub 2019 Nov 26.
50	X-linked CHARGE-like Abruzzo-Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations. Clin Genet. 2013 Apr;83(4):352-8. doi: 10.1111/j.1399-0004.2012.01930.x. Epub 2012 Aug 7.
51	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 Mar;27(3):294. doi: 10.1002/humu.9411.
52	Genetic analysis of TTF-2 gene in children with congenital hypothyroidism and cleft palate, congenital hypothyroidism, or isolated cleft palate.Thyroid. 2004 Aug;14(8):584-8. doi: 10.1089/1050725041692864.