The genetics of isolated and syndromic clubfoot

B Sadler, C A Gurnett, M B Dobbs, B Sadler, C A Gurnett, M B Dobbs

Abstract

Purpose: Congenital clubfoot is a serious birth defect that affects nearly 0.1% of all births. Though there is strong evidence for a genetic basis of isolated clubfoot, aside from a handful of associations, much of the heritability remains unexplained.

Methods: By systematically examining the genes involved in syndromic clubfoot, we may find new candidate genes and pathways to investigate in isolated clubfoot.

Results: In addition to the expected enrichment of extracellular matrix and transforming growth factor beta (TGF-β) signalling genes, we find many genes involved in syndromic clubfoot encode peroxisomal matrix proteins, as well as enzymes necessary for sulfation of proteoglycans, an important part of connective tissue. Further, the association of Filamin B with isolated clubfoot as well as syndromic clubfoot is an encouraging finding.

Conclusion: We should examine these categories for enrichment in isolated clubfoot patients to increase our understanding of the underlying biology and pathophysiology of this deformity. Understanding the spectrum of syndromes that have clubfoot as a feature enables a better understanding of the underlying pathophysiology of the disorder and directs future genetic screening efforts toward certain genes and genetic pathways.

Level of evidence: V.

Keywords: genetics; isolated clubfoot; talipes equinovarus.

References

    1. Wynne-Davies R. Genetic and environmental factors in the etiology of talipes equinovarus. Clin Orthop Relat Res 1972;84:9-13.
    1. Basit S, Khoshhal KI. Genetics of clubfoot; recent progress and future perspectives. Eur J Med Genet 2018;61:107-113.
    1. O’Shea RM, Sabatini CS. What is new in idiopathic clubfoot? Curr Rev Musculoskelet Med 2016;9:470-477.
    1. Wynne-Davies R. Family studies and the cause of congenital club foot. talipes equinovarus, talipes calcaneo-valgus and metatarsus varus. J Bone Joint Surg [Br] 1964;46-B:445-463.
    1. Gurnett CA, Boehm S, Connolly A, Reimschisel T, Dobbs MB. Impact of congenital talipes equinovarus etiology on treatment outcomes. Dev Med Child Neurol 2008;50:498-502.
    1. Lochmiller C, Johnston D, Scott A, Risman M, Hecht JT. Genetic epidemiology study of idiopathic talipes equinovarus. Am J Med Genet 1998;79:90-96.
    1. Engell V, Nielsen J, Damborg F, et al. . Heritability of clubfoot: a twin study. J Child Orthop 2014;8:37-41.
    1. Pagnotta G, Boccanera F, Rizzo G, et al. . Bilateral clubfoot in three homozygous preterm triplets. J Foot Ankle Surg 2011;50:718-720.
    1. Beals RK. Club foot in the Maori: a genetic study of 50 kindreds. N Z Med J 1978;88:144-146.
    1. Chapman C, Stott NS, Port RV, Nicol RO. Genetics of club foot in Maori and Pacific people. J Med Genet 2000;37:680-683.
    1. Ching GH, Chung CS, Nemechek RW. Genetic and epidemiological studies of clubfoot in Hawaii: ascertainment and incidence. Am J Hum Genet 1969;21:566-580.
    1. Alvarado DM, Aferol H, McCall K, et al. . Familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4. Am J Hum Genet 2010;87:154-160.
    1. Hasson P, DeLaurier A, Bennett M, et al. . Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning. Dev Cell 2010;18:148-156.
    1. Logan M, Tabin CJ. Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science 1999;283:1736-1739.
    1. Gurnett CA, Alaee F, Kruse LM, et al. . Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. Am J Hum Genet 2008;83:616-622.
    1. Lu W, Bacino CA, Richards BS, et al. . Studies of TBX4 and chromosome 17q23.1q23.2: an uncommon cause of nonsyndromic clubfoot . Am J Med Genet A 2012;158:1620-1627.
    1. Peterson JF, Ghaloul-Gonzalez L, Madan-Khetarpal S, et al. . Familial microduplication of 17q23.1–q23.2 involving TBX4 is associated with congenital clubfoot and reduced penetrance in females. Am J Med Genet A 2014;164:364-369.
    1. Alvarado DM, McCall K, Aferol H, et al. . Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Hum Mol Genet 2011;20:3943-3952.
    1. Alvarado DM, Buchan JG, Frick SL, et al. . Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development. Eur J Hum Genet 2013;21:373-380.
    1. Pineault KM, Wellik DM. Hox genes and limb musculoskeletal development. Curr Osteoporos Rep 2014;12:420-427.
    1. Wang LL, Fu WN, Li-Ling J, et al. . HOXD13 may play a role in idiopathic congenital clubfoot by regulating the expression of FHL1. Cytogenet Genome Res 2008;121:189-195.
    1. Dobbs MB, Gurnett CA, Pierce B, et al. . HOXD10 M319K mutation in a family with isolated congenital vertical talus. J Orthop Res 2006;24:448-453.
    1. Shrimpton AE, Levinsohn EM, Yozawitz JM, et al. . A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease. Am J Hum Genet 2004;75:92-96.
    1. Ester AR, Weymouth KS, Burt A, et al. . Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot. Am J Med Genet A 2009;149:2745-2752.
    1. Weymouth KS, Blanton SH, Powell T, et al. . Functional assessment of clubfoot associated HOXA9, TPM1, and TPM2 variants suggests a potential gene regulation mechanism. Clin Orthop Relat Res 2016;474:1726-1735.
    1. Alvarado DM, McCall K, Hecht JT, Dobbs MB, Gurnett CA. Deletions of 5¢ HOXC genes are associated with lower extremity malformations, including clubfoot and vertical talus. J Med Genet 2016;53:250-255.
    1. Shyy W, Wang K, Sheffield VC, Morcuende JA. Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot. J Pediatr Orthop 2010;30:231-234.
    1. Gurnett CA, Alaee F, Desruisseau D, Boehm S, Dobbs MB. Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot. Clin Orthop Relat Res 2009;467:1195-1200.
    1. Weymouth KS, Blanton SH, Bamshad MJ, et al. . Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot. Am J Med Genet A 2011;155:2170-2179.
    1. Sommer A, Blanton SH, Weymouth K, et al. . Smoking, the xenobiotic pathway, and clubfoot. Birth Defects Res A Clin Mol Teratol 2011;91:20-28.
    1. Hecht JT, Ester A, Scott A, et al. . NAT2 variation and idiopathic talipes equinovarus (clubfoot). Am J Med Genet A 2007;143:2285-2291.
    1. Sharp L, Miedzybrodzka Z, Cardy AH, et al. . The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR), maternal use of folic acid supplements, and risk of isolated clubfoot: A case-parent-triad analysis. Am J Epidemiol 2006;164:852-861.
    1. Heck AL, Bray MS, Scott A, Blanton SH, Hecht JT. Variation in CASP10 gene is associated with idiopathic talipes equinovarus. J Pediatr Orthop 2005;25:598-602.
    1. Ester AR, Tyerman G, Wise CA, Blanton SH, Hecht JT. Apoptotic gene analysis in idiopathic talipes equinovarus (clubfoot). Clin Orthop Relat Res 2007;462:32-37.
    1. Xu Q, Wu N, Cui L, Wu Z, Qiu G. Filamin B: the next hotspot in skeletal research? J Genet Genomics 2017;44:335-342.
    1. Yang H, Zheng Z, Cai H, et al. . Three novel missense mutations in the filamin B gene are associated with isolated congenital talipes equinovarus. Hum Genet 2016;135:1181-1189.
    1. Zhang TX, Haller G, Lin P, et al. . Genome-wide association study identifies new disease loci for isolated clubfoot. J Med Genet 2014;51:334-339.
    1. Lowry RB, Sibbald B, Bedard T, Hall JG. Prevalence of multiple congenital contractures including arthrogryposis multiplex congenita in Alberta, Canada, and a strategy for classification and coding. Birth Defects Res A Clin Mol Teratol 2010;88:1057-1061.
    1. Hall JG. Arthrogryposis (multiple congenital contractures): diagnostic approach to etiology, classification, genetics, and general principles. Eur J Med Genet 2014;57:464-472.
    1. Hall JG, Kimber E, van Bosse HJP. Genetics and classifications. J Pediatr Orthop 2017;37(suppl 1):S4-S8.
    1. Chong JX, Burrage LC, Beck AE, et al. . Autosomal-dominant multiple pterygium syndrome is caused by mutations in MYH3. Am J Hum Genet 2015;96:841-849.
    1. Kimber E, Tajsharghi H, Kroksmark AK, Oldfors A, Tulinius M. A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis. Neurology 2006;67:597-601.
    1. Kimber E, Tajsharghi H, Kroksmark AK, Oldfors A, Tulinius M. Distal arthrogryposis: clinical and genetic findings. Acta Paediatr 2012;101:877-887.
    1. Toydemir RM, Rutherford A, Whitby FG, et al. . Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet 2006;38:561-565.
    1. Coste B, Houge G, Murray MF, et al. . Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. Proc Natl Acad Sci USA 2013;110:4667-4672.
    1. McMillin MJ, Beck AE, Chong JX, et al. . Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet 2014;94:734-744.
    1. Delle Vedove A, Storbeck M, Heller R, et al. . Biallelic loss of proprioception-related PIEZO2 causes muscular atrophy with perinatal respiratory distress, arthrogryposis, and scoliosis. Am J Hum Genet 2016;99:1406-1408.
    1. Bertoli-Avella AM, Gillis E, Morisaki H, et al. . Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol 2015;65:1324-1336.
    1. De Cario R, Sticchi E, Lucarini L, et al. . Role of TGFBR1 and TGFBR2 genetic variants in Marfan syndrome. J Vasc Surg 2018;68:225-233.
    1. Schepers D, Doyle AJ, Oswald G, et al. . The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome. Eur J Hum Genet 2015;23:224-228.
    1. Valenzuela I, Fernández-Alvarez P, Munell F, et al. . Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a novel TGFBR2 mutation. Eur J Med Genet 2017;60:303-307.
    1. Dawson K, Seeman P, Sebald E, et al. . GDF5 is a second locus for multiple-synostosis syndrome. Am J Hum Genet 2006;78:708-712.
    1. Hynes RO. The extracellular matrix: not just pretty fibrils. Science 2009;326:1216-1219.
    1. Czarny-Ratajczak M, Lohiniva J, Rogala P, et al. . A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet 2001;69:969-980.
    1. Zhou T, Wang Y, Zhou H, et al. . Dual novel mutations in SLC26A2 in two siblings with multiple epiphyseal dysplasia 4 from a Chinese family: a case report. BMC Med Genet 2018;19:70.
    1. Bonafé L, Hästbacka J, de la Chapelle A, et al. . A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia. J Med Genet 2008;45:827-831.
    1. Sakai LY, Keene DR, Renard M, De Backer J. FBN1: the disease-causing gene for Marfan syndrome and other genetic disorders. Gene 2016;591:279-291.
    1. Simons C, Griffin LB, Helman G, et al. . Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect. Am J Hum Genet 2015;96:675-681.
    1. Waterham HR, Ferdinandusse S, Wanders RJ. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta 2016;1863:922-933.
    1. Weller S, Cajigas I, Morrell J, et al. . Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis. Am J Hum Genet 2005;76:987-1007.
    1. Hermanns P, Unger S, Rossi A, et al. . Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis. Am J Hum Genet 2008;82:1368-1374.
    1. Janecke AR, Li B Boehm M, et al. . The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations. Am J Med Genet A 2016;170:103-115.
    1. Syx D, Van Damme T, Symoens S, et al. . Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis. Hum Mutat 2015;36:535-547.
    1. Uehara M, Kosho T, Yamamoto N, et al. . Spinal manifestations in 12 patients with musculocontractural Ehlers-Danlos syndrome caused by CHST14/D4ST1 deficiency (mcEDS-CHST14). Am J Med Genet A 2018;176:2331-2341.
    1. Waryah AM, Shahzad M, Shaikh H, et al. . A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss in Pakistani kindred. Clin Genet 2016;90:90-95.
    1. Ferreira CR, Xia ZJ, Clément A, et al. . A recurrent de novo heterozygous COG4 substitution leads to Saul-Wilson Syndrome, disrupted vesicular trafficking, and altered proteoglycan glycosylation. Am J Hum Genet 2018;103:553-567.
    1. Ehmke N, Caliebe A, Koenig R, et al. . Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome. Am J Hum Genet 2014;95:763-770.
    1. Manzke H, Lehmann K, Klopocki E, Caliebe A. Catel-Manzke syndrome: two new patients and a critical review of the literature. Eur J Med Genet 2008;51:452-465.
    1. Krakow D, Robertson SP, King LM, et al. . Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 2004;36:405-410.
    1. Unger S, Lausch E, Rossi A, et al. . Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features. Am J Med Genet A 2010;152:2543-2549.
    1. Zapała B, Płatek T, Wybrańska I. A novel TAZ gene mutation and mosaicism in a Polish family with Barth syndrome. Ann Hum Genet 2015;79:218-224.
    1. Lv F, Xu X, Song Y, et al. . Novel mutations in PLOD2 cause rare Bruck Syndrome. Calcif Tissue Int 2018;102:296-309.
    1. Di Gioia SA, Connors S, Matsunami N, et al. . A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun 2017;8:16077.
    1. Okamoto Y, Goksungur MT, Pehlivan D, et al. . Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D. Genet Med 2014;16:386-394.
    1. Kosho T. CHST14/D4ST1 deficiency: new form of Ehlers-Danlos syndrome. Pediatr Int (Roma) 2016;58:88-99.
    1. Palmeri S, Mari F, Meloni I, et al. . Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism. Clin Genet 2003;63:510-515.
    1. Sang L, Miller JJ, Corbit KC, et al. . Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 2011;145:513-528.
    1. McClure P, Kilinc E, Oishi S, et al. . Mobius Syndrome: a 35-year single institution experience. J Pediatr Orthop 2017;37:e446-e449.
    1. Tomas-Roca L, Tsaalbi-Shtylik A, Jansen JG, et al. . De novo mutations in PLXND1 and REV3L cause Möbius syndrome. Nat Commun 2015;6:7199.
    1. Bouhouche A, Birouk N, Azzedine H, et al. . Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families. Brain 2007;130:1062-1075.
    1. Lehalle D, Wieczorek D, Zechi-Ceide RM, et al. . A review of craniofacial disorders caused by spliceosomal defects. Clin Genet 2015;88:405-415.
    1. Alves LU, Santos S, Musso CM, et al. . Santos syndrome is caused by mutation in the WNT7A gene. J Hum Genet 2017;62:1073-1078.
    1. Johnston JJ, Sapp JC, Curry C, et al. . Expansion of the TARP syndrome phenotype associated with de novo mutations and mosaicism. Am J Med Genet A 2014;164:120-128.
    1. Cappello S, Gray MJ, Badouel C, et al. . Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nat Genet 2013;45:1300-1308.

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