Details of Disease

General Information of Disease (ID: DISLXT4S)

• Disease Name: Clubfoot
• Synonyms: CCF; clubfoot, congenital, with or without deficiency of long bones and/or mirror-IMAGE polydactyly; talipes equinovarus; congenital clubfoot; congenital talipes equinovarus; talipes; clubbed foot; club foot; congenital equinovarus; equinovarus deformity of foot (finding); equinovarus deformity of foot
• Definition: The most common congenital deformation of the foot, occurring in 1 of 1,000 live births. The most common form is talipes equinovarus, where the deformed foot is turned downward and inward sharply.
• Disease Hierarchy:
  DIS5M94B: Non-syndromic limb reduction defect
  DISVV3CF: Familial clubfoot with or without associated lower limb anomalies
  DISLXT4S: Clubfoot
• Disease Identifiers:
  MONDO ID: MONDO_0007342
  MESH ID: D003025
  UMLS CUI: C0009081
  MedGen ID: 3130
  HPO ID: HP:0001762
  SNOMED CT ID: 1156475005

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 8 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
MTHFR	TTQWOU1	Limited	Genetic Variation	[1]
WNT7A	TT8NARC	Limited	Biomarker	[2]
BRIP1	TTZV7LJ	Strong	Genetic Variation	[3]
CDK13	TTRIM0E	Strong	Genetic Variation	[4]
KYNU	TTWQM3J	Strong	CausalMutation	[5]
MYH2	TTBIL13	Strong	Altered Expression	[6]
TRPV4	TTKP2SU	Strong	Genetic Variation	[7]
GDF5	TT37XV9	Definitive	Genetic Variation	[8]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC26A2	DTFSLX5	moderate	Genetic Variation	[9]

This Disease Is Related to 2 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
AKR1C1	DE7P2FB	Strong	Genetic Variation	[10]
CHST3	DEQIZP2	Strong	Genetic Variation	[11]

This Disease Is Related to 26 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
FLNB	OTPCOYL6	Limited	Biomarker	[12]
RBM10	OTES2MES	Limited	Genetic Variation	[13]
RFLNA	OT6GS3XQ	Limited	Genetic Variation	[14]
TPM2	OTA1L0P8	Limited	Genetic Variation	[15]
COL9A1	OTWBR27Y	Disputed	Genetic Variation	[16]
HOXA9	OTKNK5H0	Disputed	Genetic Variation	[17]
GLI3	OTKDOE94	moderate	Biomarker	[18]
LMX1B	OTM8145D	moderate	Biomarker	[19]
CAND2	OTOMOG3R	Strong	Biomarker	[2]
CHST14	OT3FLH7U	Strong	Genetic Variation	[20]
CILP2	OTAFSWG1	Strong	Biomarker	[21]
EIF4A3	OTYYFE7K	Strong	Biomarker	[22]
FKBP8	OT8RPSOC	Strong	Biomarker	[23]
FRAS1	OTLPESF3	Strong	Biomarker	[24]
HOXC11	OT8NMHM6	Strong	Genetic Variation	[25]
HOXC12	OTGG9BJS	Strong	Genetic Variation	[25]
HOXD12	OTKRUPGV	Strong	Biomarker	[26]
MYH14	OT1TZEJK	Strong	Genetic Variation	[6]
NACA2	OT23700G	Strong	Biomarker	[3]
NCOR2	OTY917X0	Strong	Genetic Variation	[14]
PITX1	OTA0UN4C	Strong	Autosomal dominant	[27]
RBBP8	OTRHJ3GI	Strong	Genetic Variation	[28]
SOX9	OTVDJFGN	Strong	Altered Expression	[29]
TBX4	OTW58FG4	Strong	Genetic Variation	[30]
TNNT3	OT4C498E	Strong	Genetic Variation	[31]
MYH8	OT9F350W	Definitive	Biomarker	[32]

References

• [1] Whole genome sequencing identifies ANXA3 and MTHFR mutations in a large family with an unknown equinus deformity associated genetic disorder.Mol Biol Rep. 2016 Oct;43(10):1147-55. doi: 10.1007/s11033-016-4047-2. Epub 2016 Jul 30.
• [2] Evaluation of CAND2 and WNT7a as candidate genes for congenital idiopathic clubfoot.Clin Orthop Relat Res. 2009 May;467(5):1201-5. doi: 10.1007/s11999-008-0701-x. Epub 2009 Jan 22.
• [3] Studies of TBX4 and chromosome 17q23.1q23.2: an uncommon cause of nonsyndromic clubfoot.Am J Med Genet A. 2012 Jul;158A(7):1620-7. doi: 10.1002/ajmg.a.35418. Epub 2012 Jun 7.
• [4] Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.Genome Med. 2017 Aug 14;9(1):73. doi: 10.1186/s13073-017-0463-8.
• [5] NAD Deficiency, Congenital Malformations, and Niacin Supplementation. N Engl J Med. 2017 Aug 10;377(6):544-552.
• [6] Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot.J Pediatr Orthop. 2010 Apr-May;30(3):231-4. doi: 10.1097/BPO.0b013e3181d35e3f.
• [7] Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy.Neurology. 2014 May 27;82(21):1919-26. doi: 10.1212/WNL.0000000000000450. Epub 2014 Apr 30.
• [8] Magnetic resonance angiography in clubfoot and vertical talus: a feasibility study.Clin Orthop Relat Res. 2009 May;467(5):1250-5. doi: 10.1007/s11999-008-0673-x. Epub 2009 Jan 6.
• [9] A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet. 2001 Nov;69(5):969-80. doi: 10.1086/324023. Epub 2001 Sep 14.
• [10] Parental internet search in the field of pediatric orthopedics.Eur J Pediatr. 2019 Jun;178(6):929-935. doi: 10.1007/s00431-019-03369-w. Epub 2019 Apr 10.
• [11] Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype.Am J Med Genet A. 2008 Sep 15;146A(18):2376-84. doi: 10.1002/ajmg.a.32482.
• [12] Filamin B: The next hotspot in skeletal research?.J Genet Genomics. 2017 Jul 20;44(7):335-342. doi: 10.1016/j.jgg.2017.04.007. Epub 2017 Jul 6.
• [13] Clinical diagnostic exome evaluation for an infant with a lethal disorder: genetic diagnosis of TARP syndrome and expansion of the phenotype in a patient with a newly reported RBM10 alteration.BMC Med Genet. 2017 Jun 2;18(1):60. doi: 10.1186/s12881-017-0426-3.
• [14] Genome-wide association study identifies new disease loci for isolated clubfoot.J Med Genet. 2014 May;51(5):334-9. doi: 10.1136/jmedgenet-2014-102303. Epub 2014 Mar 25.
• [15] Functional Assessment of Clubfoot Associated HOXA9, TPM1, and TPM2 Variants Suggests a Potential Gene Regulation Mechanism.Clin Orthop Relat Res. 2016 Jul;474(7):1726-35. doi: 10.1007/s11999-016-4788-1. Epub 2016 Mar 28.
• [16] Role of COL9A1 genetic polymorphisms in development of congenital talipes equinovarus in a Chinese population.Genet Mol Res. 2016 Nov 3;15(4). doi: 10.4238/gmr15048773.
• [17] HOXA9 rs3801776 G>A polymorphism increases congenital talipes equinovarus risk in a Chinese population.J Gene Med. 2019 Oct;21(10):e3119. doi: 10.1002/jgm.3119. Epub 2019 Aug 30.
• [18] The expression of Gli3, regulated by HOXD13, may play a role in idiopathic congenital talipes equinovarus.BMC Musculoskelet Disord. 2009 Nov 19;10:142. doi: 10.1186/1471-2474-10-142.
• [19] Nail-patella syndrome, infantile nephrotic syndrome: complete remission with antiproteinuric treatment.Nephrol Dial Transplant. 2009 Apr;24(4):1335-8. doi: 10.1093/ndt/gfn725. Epub 2009 Jan 15.
• [20] Defect in dermatan sulfate in urine of patients with Ehlers-Danlos syndrome caused by a CHST14/D4ST1 deficiency.Clin Biochem. 2017 Aug;50(12):670-677. doi: 10.1016/j.clinbiochem.2017.02.018. Epub 2017 Feb 24.
• [21] Novel contribution to clubfoot pathogenesis: The possible role of extracellular matrix proteins.J Orthop Res. 2019 Mar;37(3):769-778. doi: 10.1002/jor.24211. Epub 2019 Feb 12.
• [22] Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice.Development. 1998 Mar;125(5):813-24. doi: 10.1242/dev.125.5.813.
• [23] Regulation of apoptosis and neurite extension by FKBP38 is required for neural tube formation in the mouse.Genes Cells. 2008 Jun;13(6):635-51. doi: 10.1111/j.1365-2443.2008.01194.x. Epub 2008 May 4.
• [24] Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet. 2003 Jun;34(2):203-8. doi: 10.1038/ng1142.
• [25] Deletions of 5' HOXC genes are associated with lower extremity malformations, including clubfoot and vertical talus.J Med Genet. 2016 Apr;53(4):250-5. doi: 10.1136/jmedgenet-2015-103505. Epub 2016 Jan 4.
• [26] [Analysis of association between 5' HOXD gene and idiopathic congenital talipes equinovarus].Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005 Dec;22(6):653-6.
• [27] Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. Am J Hum Genet. 2008 Nov;83(5):616-22. doi: 10.1016/j.ajhg.2008.10.004. Epub 2008 Oct 23.
• [28] RBBP8 syndrome with microcephaly, intellectual disability, short stature and brachydactyly. Am J Med Genet A. 2015 Dec;167A(12):3148-52. doi: 10.1002/ajmg.a.37299. Epub 2015 Sep 3.
• [29] All-trans-retinoic acid activates SDF-1/CXCR4/ROCK2 signaling pathway to inhibit chondrogenesis.Am J Transl Res. 2017 May 15;9(5):2296-2305. eCollection 2017.
• [30] Genetics of clubfoot; recent progress and future perspectives.Eur J Med Genet. 2018 Feb;61(2):107-113. doi: 10.1016/j.ejmg.2017.09.006. Epub 2017 Sep 14.
• [31] Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot.Clin Orthop Relat Res. 2009 May;467(5):1195-200. doi: 10.1007/s11999-008-0694-5. Epub 2009 Jan 14.
• [32] Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot.Am J Med Genet A. 2011 Sep;155A(9):2170-9. doi: 10.1002/ajmg.a.34167. Epub 2011 Aug 10.