Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Pediatric Orthogenomics: The Latest Trends and Controversies

1 Department of Orthopaedic Surgery, Geisinger Medical Center, Danville, PA, USA;
2 Department of Pediatrics, Geisinger Medical Center, Danville, PA, USA

The advent of molecular biology has paved way for an era of personalized medicine. Though medical disciplines such as oncology and cardiology are advanced in their use of genomics, implementation has been slower in other specialties, such as orthopaedics. Recent advances in genomic technology have shed light on the underlying genetic basis of various pediatric orthopaedic disorders. Prior understanding of the genetic makeup of a patient may help individualize care in patients with conditions including idiopathic scoliosis, congenital talipes equinovarus and congenital limb deformities. The fastpaced growth of information in orthogenomics often makes it challenging for an orthopaedic surgeon to effectively use this information for patient care. Genetic characterization of a patient will help indicate risk of progression of a condition, recurrence and/or response to a treatment modality, and a collaborative approach between an orthopaedic surgeon and a geneticist can help tailor patient care. The following review article summarizes current understanding in molecular genomics of common pediatric orthopaedic disorders.
  Article Metrics

Keywords pediatric orthogenomics; adolescent idiopathic scoliosis; congenital limb deformity; congenital talipes equinovarus

Citation: Neha Sinha, Mark A. Seeley, Daniel S. Horwitz, Hemil Maniar, Andrea H. Seeley. Pediatric Orthogenomics: The Latest Trends and Controversies. AIMS Medical Science, 2017, 4(2): 192-216. doi: 10.3934/medsci.2017.2.192


  • 1. Eknoyan G (2006) On the origin of genetics and beginnings of medical genetics of diseases of the kidney. Adv Chronic Kidney Dis 13: 174-177.    
  • 2. Keller EF (2002, Print) The Century of the Gene. Cambridge, MA: Harvard UP, 2002.
  • 3. Portin P (2014) The birth and development of the DNA theory of inheritance: sixty years since the discovery of the structure of DNA. J Genet 93: 293-302.    
  • 4. Mullis KB (1990) The unusual origin of the polymerase chain reaction. Sci Am 262: 56-61, 64-5.    
  • 5. Sweeney BP (2004) Watson and Crick 50 years on. From double helix to pharmacogenomics. Anaesthesia 59: 150-165.
  • 6. Evans CH, Rosier RN (2005) Molecular biology in orthopaedics: the advent of molecular orthopaedics. J Bone Joint Surg Am 87: 2550-2564.
  • 7. Puzas JE, O'Keefe RJ, Lieberman JR (2002) The orthopaedic genome: what does the future hold and are we ready?. J Bone Joint Surg Am 84-A: 133-141.
  • 8. Bayat A, Barton A, Ollier WE (2004) Dissection of complex genetic disease: implications for orthopaedics. Clin Orthop Relat Res (419): 297-305.
  • 9. Matzko ME, Bowen TR, Smith WR (2012) Orthogenomics: an update. J Am Acad Orthop Surg 20: 536-546.    
  • 10. Riegel M (2014) Human molecular cytogenetics: From cells to nucleotides. Genet Mol Biol 37: 194-209.    
  • 11. Langer-Safer PR, Levine M, Ward DC (1982) Immunological method for mapping genes on Drosophila polytene chromosomes. Proc Natl Acad Sci U S A 79: 4381-4385.    
  • 12. Kallioniemi A, Kallioniemi OP, Sudar D, et al. (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258: 818-821.    
  • 13. Pinkel D, Segraves R, Sudar D, et al. (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20: 207-211.    
  • 14. Solinas-Toldo S, Lampel S, Stilgenbauer S, et al. (1997) Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20: 399-407.    
  • 15. Wiszniewska J, Bi W, Shaw C, et al. (2014) Combined array CGH plus SNP genome analyses in a single assay for optimized clinical testing. Eur J Hum Genet 22: 79-87.    
  • 16. Shashi V, McConkie-Rosell A, Rosell B, et al. (2014) The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet Med 16: 176-182.    
  • 17. Ogilvie J (2010) Adolescent idiopathic scoliosis and genetic testing. Curr Opin Pediatr 22: 67-70.    
  • 18. Horne JP, Flannery R, Usman S (2014) Adolescent idiopathic scoliosis: diagnosis and management. Am Fam Physician 89: 193-198.
  • 19. Riseborough EJ, Wynne-Davies R (1973) A genetic survey of idiopathic scoliosis in Boston, Massachusetts. J Bone Joint Surg Am 55: 974-982.    
  • 20. Kesling KL, Reinker KA (1997) Scoliosis in twins. A meta-analysis of the literature and report of six cases. Spine (Phila Pa 1976) 22: 2009-2014;
  • 21. Wu J, Qiu Y, Zhang L, et al. (2006) Association of estrogen receptor gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 31: 1131-1136.    
  • 22. Chen S, Zhao L, Roffey DM, et al. (2014) Association between the ESR1-351A > G single nucleotide polymorphism (rs9340799) and adolescent idiopathic scoliosis: a systematic review and meta-analysis. Eur Spine J 23: 2586-2593.    
  • 23. Zhao L, Roffey DM, Chen S (2016) Association between the Estrogen Receptor Beta (ESR2) Rs1256120 Single Nucleotide Polymorphism and Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-Analysis. Spine (Phila Pa 1976): Epub ahead of print.
  • 24. Yang P, Liu H, Lin J, et al. (2015) The Association of rs4753426 Polymorphism in the Melatonin Receptor 1B (MTNR1B) Gene and Susceptibility to Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-analysis. Pain Physician 18: 419-431.
  • 25. Ogura Y, Kou I, Miura S, et al. (2015) A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. Am J Hum Genet 97: 337-342.    
  • 26. Buchan JG, Alvarado DM, Haller GE, et al. (2014) Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet 23: 5271-5282.    
  • 27. Liu Z, Wang F, Xu LL, et al. (2015) Polymorphism of rs2767485 in Leptin Receptor Gene is Associated With the Occurrence of Adolescent Idiopathic Scoliosis. Spine (Phila Pa 1976) 40: 1593-1598.    
  • 28. Zhou S, Qiu XS, Zhu ZZ, et al. (2012) A single-nucleotide polymorphism rs708567 in the IL-17RC gene is associated with a susceptibility to and the curve severity of adolescent idiopathic scoliosis in a Chinese Han population: a case-control study. BMC Musculoskelet Disord 13: 181-2474-13-181.    
  • 29. Ryzhkov II, Borzilov EE, Churnosov MI, et al. (2013) Transforming growth factor beta 1 is a novel susceptibility gene for adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 38: E699-704.    
  • 30. Zhang H, Zhao S, Zhao Z, et al. (2014) The association of rs1149048 polymorphism in matrilin-1(MATN1) gene with adolescent idiopathic scoliosis susceptibility: a meta-analysis. Mol Biol Rep 41: 2543-2549.    
  • 31. Bae JW, Cho CH, Min WK, et al. (2012) Associations between matrilin-1 gene polymorphisms and adolescent idiopathic scoliosis curve patterns in a Korean population. Mol Biol Rep 39: 5561-5567.    
  • 32. Yu Y, Chen ZJ, Qiu Y, et al. (2009) Association between matrilin-1 gene polymorphism and bracing effectiveness in adolescent idiopathic scoliosis girls. Zhonghua Wai Ke Za Zhi 47: 1728-1731.
  • 33. Wang B, Chen ZJ, Qiu Y, et al. (2009) Decreased circulating matrilin-1 levels in adolescent idiopathic scoliosis. Zhonghua Wai Ke Za Zhi 47: 1638-1641.
  • 34. Chen ZJ, Qiu Y, Yu Y, et al. (2009) Association between polymorphism of Matrilin-1 gene (MATN1) with susceptibility to adolescent idiopathic scoliosis. Zhonghua Wai Ke Za Zhi 47: 1332-1335.
  • 35. Montanaro L, Parisini P, Greggi T, et al. (2006) Evidence of a linkage between matrilin-1 gene (MATN1) and idiopathic scoliosis. Scoliosis 1: 21.    
  • 36. Wang H, Wu Z, Zhuang Q, et al. (2008) Association study of tryptophan hydroxylase 1 and arylalkylamine N-acetyltransferase polymorphisms with adolescent idiopathic scoliosis in Han Chinese. Spine (Phila Pa 1976) 33: 2199-2203.    
  • 37. Gorman KF, Julien C, Moreau A (2012) The genetic epidemiology of idiopathic scoliosis. Eur Spine J 21: 1905-1919.    
  • 38. Zhu Z, Xu L, Qiu Y (2015) Current progress in genetic research of adolescent idiopathic scoliosis. Ann Transl Med 3: S19.
  • 39. Pearson TA, Manolio TA (2008) How to interpret a genome-wide association study. JAMA 299: 1335-1344.    
  • 40. Chettier R, Nelson L, Ogilvie JW, et al. (2015) Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis. PLoS One 10: e0117708.    
  • 41. Ikegawa S (2016) Genomic study of adolescent idiopathic scoliosis in Japan. Scoliosis Spinal Disord 11: 5-016-0067-x.    
  • 42. Grauers A, Wang J, Einarsdottir E, et al. (2015) Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis. Spine J 15: 2239-2246.    
  • 43. Jagla K, Dolle P, Mattei MG, et al. (1995) Mouse Lbx1 and human LBX1 define a novel mammalian homeobox gene family related to the Drosophila lady bird genes. Mech Dev 53: 345-356.    
  • 44. Gross MK, Moran-Rivard L, Velasquez T, et al. (2000) Lbx1 is required for muscle precursor migration along a lateral pathway into the limb. Development 127: 413-424.
  • 45. Schafer K, Neuhaus P, Kruse J, et al. (2003) The homeobox gene Lbx1 specifies a subpopulation of cardiac neural crest necessary for normal heart development. Circ Res 92: 73-80.    
  • 46. Gross MK, Dottori M, Goulding M (2002) Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34: 535-549.    
  • 47. Xu JF, Yang GH, Pan XH, et al. (2015) Association of GPR126 gene polymorphism with adolescent idiopathic scoliosis in Chinese populations. Genomics 105: 101-107.    
  • 48. Kou I, Takahashi Y, Johnson TA, et al. (2013) Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet 45: 676-679.    
  • 49. Zhao L, Roffey DM, Chen S (2015) Genetics of adolescent idiopathic scoliosis in the post-genome-wide association study era. Ann Transl Med 3: S35.
  • 50. Stankiewicz P, Lupski JR (2010) Structural variation in the human genome and its role in disease. Annu Rev Med 61: 437-455.    
  • 51. Buchan JG, Alvarado DM, Haller G, et al. (2014) Are copy number variants associated with adolescent idiopathic scoliosis?. Clin Orthop Relat Res 472: 3216-3225.    
  • 52. Costell M, Gustafsson E, Aszodi A, et al. (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147: 1109-1122.    
  • 53. Rodgers KD, Sasaki T, Aszodi A, et al. (2007) Reduced perlecan in mice results in chondrodysplasia resembling Schwartz-Jampel syndrome. Hum Mol Genet 16: 515-528.    
  • 54. Stum M, Davoine CS, Vicart S, et al. (2006) Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome. Hum Mutat 27: 1082-1091.    
  • 55. Baschal EE, Wethey CI, Swindle K, et al. (2014) Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis. G3 (Bethesda) 5: 167-174.
  • 56. Robinson PN, Godfrey M (2000) The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet 37: 9-25.    
  • 57. Tuncbilek E, Alanay Y (2006) Congenital contractural arachnodactyly (Beals syndrome). Orphanet J Rare Dis 1: 20.    
  • 58. Patten SA, Margaritte-Jeannin P, Bernard JC, et al. (2015) Functional variants of POC5 identified in patients with idiopathic scoliosis. J Clin Invest 125: 1124-1128.
  • 59. Li W, Li Y, Zhang L, et al. (2016) AKAP2 identified as a novel gene mutated in a Chinese family with adolescent idiopathic scoliosis. J Med Genet 53: 488-493.    
  • 60. Weinstein SL, Dolan LA, Wright JG, et al. (2013) Effects of bracing in adolescents with idiopathic scoliosis. N Engl J Med 369: 1512-1521.    
  • 61. Ward K, Ogilvie JW, Singleton MV, et al. (2010) Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 35: E1455-1464.    
  • 62. Roye BD, Wright ML, Matsumoto H, et al. (2015) An Independent Evaluation of the Validity of a DNA-Based Prognostic Test for Adolescent Idiopathic Scoliosis. J Bone Joint Surg Am 97: 1994-1998.    
  • 63. Lee MC (2015) The Distance from Bench to Bedside: Commentary on an article by Benjamin D. Roye, MD, MPH, et al..: "An Independent Evaluation of the Validity of a DNA-Based Prognostic Test for Adolescent Idiopathic Scoliosis". J Bone Joint Surg Am 97: e79.
  • 64. Tang QL, Julien C, Eveleigh R, et al. (2015) A replication study for association of 53 single nucleotide polymorphisms in ScoliScore test with adolescent idiopathic scoliosis in French-Canadian population. Spine (Phila Pa 1976) 40: 537-543.    
  • 65. Bohl DD, Telles CJ, Ruiz FK, et al. (2016) A Genetic Test Predicts Providence Brace Success for Adolescent Idiopathic Scoliosis When Failure Is Defined as Progression to >45 Degrees. Clin Spine Surg 29: E146-50.
  • 66. Xu L, Qiu X, Sun X, et al. (2011) Potential genetic markers predicting the outcome of brace treatment in patients with adolescent idiopathic scoliosis. Eur Spine J 20: 1757-1764.    
  • 67. Lowry RB, Bedard T (2016) Congenital limb deficiency classification and nomenclature: The need for a consensus. Am J Med Genet A 170: 1400-1404.    
  • 68. Gold NB, Westgate MN, Holmes LB (2011) Anatomic and etiological classification of congenital limb deficiencies. Am J Med Genet A 155A: 1225-1235.
  • 69. Auerbach AD, Allen RG (1991) Leukemia and preleukemia in Fanconi anemia patients. A review of the literature and report of the International Fanconi Anemia Registry. Cancer Genet Cytogenet 51: 1-12.
  • 70. Hurst JA, Hall CM, Baraitser M (1991) The Holt-Oram syndrome. J Med Genet 28: 406-410.    
  • 71. Hall JG (1987) Thrombocytopenia and absent radius (TAR) syndrome. J Med Genet 24: 79-83.    
  • 72. Barham G, Clarke NM (2008) Genetic regulation of embryological limb development with relation to congenital limb deformity in humans. J Child Orthop 2: 1-9.
  • 73. Zuniga A, Zeller R, Probst S (2012) The molecular basis of human congenital limb malformations. Wiley Interdiscip Rev Dev Biol 1: 803-822.    
  • 74. Wang YH, Keenan SR, Lynn J, et al. (2015) Gremlin1 induces anterior-posterior limb bifurcations in developing Xenopus limbs but does not enhance limb regeneration. Mech Dev 138 Pt 3: 256-267.
  • 75. Amprino R, Bonetti DA (1967) Experimental observations in the development of ectoderm-free mesoderm of the limb bud in chick embryos. Nature 214: 826-827.
  • 76. Brewer JR, Mazot P, Soriano P (2016) Genetic insights into the mechanisms of Fgf signaling. Genes Dev 30: 751-771.    
  • 77. Manouvrier-Hanu S, Holder-Espinasse M, Lyonnet S (1999) Genetics of limb anomalies in humans. Trends Genet 15: 409-417.    
  • 78. Sun X, Mariani FV, Martin GR (2002) Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418: 501-508.    
  • 79. Boulet AM, Moon AM, Arenkiel BR, et al. (2004) The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Dev Biol 273: 361-372.    
  • 80. Zeller R, Zuniga A (2007) Shh and Gremlin1 chromosomal landscapes in development and disease. Curr Opin Genet Dev 17: 428-434.    
  • 81. Khokha MK, Hsu D, Brunet LJ, et al. (2003) Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nat Genet 34: 303-307.    
  • 82. Dimitrov BI, Voet T, De Smet L, et al. (2010) Genomic rearrangements of the GREM1-FMN1 locus cause oligosyndactyly, radio-ulnar synostosis, hearing loss, renal defects syndrome and Cenani--Lenz-like non-syndromic oligosyndactyly. J Med Genet 47: 569-574.    
  • 83. Gong Y, Krakow D, Marcelino J, et al. (1999) Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 21: 302-304.    
  • 84. Walsh DW, Godson C, Brazil DP, et al. (2010) Extracellular BMP-antagonist regulation in development and disease: tied up in knots. Trends Cell Biol 20: 244-256.    
  • 85. Garavelli L, Wischmeijer A, Rosato S, et al. (2011) Al-Awadi-Raas-Rothschild (limb/pelvis/uterus-hypoplasia/aplasia) syndrome and WNT7A mutations: genetic homogeneity and nosological delineation. Am J Med Genet A 155A: 332-336.
  • 86. Mortlock DP, Innis JW (1997) Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet 15: 179-180.    
  • 87. Goodman FR (2002) Limb malformations and the human HOX genes. Am J Med Genet 112: 256-265.    
  • 88. Duboc V, Logan MP (2011) Regulation of limb bud initiation and limb-type morphology. Dev Dyn 240: 1017-1027.    
  • 89. King M, Arnold JS, Shanske A, et al. (2006) T-genes and limb bud development. Am J Med Genet A 140: 1407-1413.
  • 90. Liu C, Nakamura E, Knezevic V, et al. (2003) A role for the mesenchymal T-box gene Brachyury in AER formation during limb development. Development 130: 1327-1337.    
  • 91. Bamshad M, Lin RC, Law DJ, et al. (1997) Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 16: 311-315.    
  • 92. Davenport TG, Jerome-Majewska LA, Papaioannou VE (2003) Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 130: 2263-2273.    
  • 93. Rallis C, Del Buono J, Logan MP (2005) Tbx3 can alter limb position along the rostrocaudal axis of the developing embryo. Development 132: 1961-1970.    
  • 94. Don EK, de Jong-Curtain TA, Doggett K, et al. (2016) Genetic basis of hindlimb loss in a naturally occurring vertebrate model. Biol Open 5: 359-366.    
  • 95. Ahn DG, Kourakis MJ, Rohde LA, et al. (2002) T-box gene tbx5 is essential for formation of the pectoral limb bud. Nature 417: 754-758.    
  • 96. Kiefer SM, Robbins L, Barina A, et al. (2008) SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes. Hum Mutat 29: 1133-1140.    
  • 97. Kohlhase J, Wischermann A, Reichenbach H, et al. (1998) Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet 18: 81-83.    
  • 98. Al-Qattan MM (2011) WNT pathways and upper limb anomalies. J Hand Surg Eur Vol 36: 9-22.
  • 99. Sowinska-Seidler A, Socha M, Jamsheer A (2014) Split-hand/foot malformation-molecular cause and implications in genetic counseling. J Appl Genet 55: 105-115.    
  • 100. Naveed M, Nath SK, Gaines M, et al. (2007) Genomewide linkage scan for split-hand/foot malformation with long-bone deficiency in a large Arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1. Am J Hum Genet 80: 105-111.    
  • 101. Gurnett CA, Dobbs MB, Nordsieck EJ, et al. (2006) Evidence for an additional locus for split hand/foot malformation in chromosome region 8q21.11-q22.3. Am J Med Genet A 140: 1744-1748.
  • 102. Jiang B, Zhang Z, Zheng P, et al. (2014) Apoptotic genes expression in placenta of clubfoot-like fetus pregnant rats. Int J Clin Exp Pathol 7: 677-684.
  • 103. Alderman BW, Takahashi ER, LeMier MK (1991) Risk indicators for talipes equinovarus in Washington State, 1987-1989. Epidemiology 2: 289-292.    
  • 104. Chung CS, Nemechek RW, Larsen IJ, et al. (1969) Genetic and epidemiological studies of clubfoot in Hawaii. General and medical considerations. Hum Hered 19: 321-342.
  • 105. Moorthi RN, Hashmi SS, Langois P, et al. (2005) Idiopathic talipes equinovarus (ITEV) (clubfeet) in Texas. Am J Med Genet A 132A: 376-380.    
  • 106. Miedzybrodzka Z (2003) Congenital talipes equinovarus (clubfoot): a disorder of the foot but not the hand. J Anat 202: 37-42.    
  • 107. Irani RN, Sherman MS (1972) The pathological anatomy of idiopathic clubfoot. Clin Orthop Relat Res 84: 14-20.    
  • 108. Bacino CA, Hecht JT (2014) Etiopathogenesis of equinovarus foot malformations. Eur J Med Genet 57: 473-479.    
  • 109. Parker SE, Mai CT, Strickland MJ, et al. (2009) Multistate study of the epidemiology of clubfoot. Birth Defects Res A Clin Mol Teratol 85: 897-904.    
  • 110. Rogers JM (2009) Tobacco and pregnancy. Reprod Toxicol 28: 152-160.    
  • 111. Lambers DS, Clark KE (1996) The maternal and fetal physiologic effects of nicotine. Semin Perinatol 20: 115-126.    
  • 112. Hecht JT, Ester A, Scott A, et al. (2007) NAT2 variation and idiopathic talipes equinovarus (clubfoot). Am J Med Genet A 143A: 2285-2291.    
  • 113. Sommer A, Blanton SH, Weymouth K, et al. (2011) Smoking, the xenobiotic pathway, and clubfoot. Birth Defects Res A Clin Mol Teratol 91: 20-28.    
  • 114. 114. Engell V, Damborg F, Andersen M, et al. (2006) Club foot: a twin study. J Bone Joint Surg Br 88: 374-376.
  • 115. de Andrade M, Barnholtz JS, Amos CI, et al. (1998) Segregation analysis of idiopathic talipes equinovarus in a Texan population. Am J Med Genet 79: 97-102.    
  • 116. Honein MA, Paulozzi LJ, Moore CA (2000) Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction. Am J Epidemiol 152: 658-665.    
  • 117. Gurnett CA, Alaee F, Kruse LM, et al. (2008) Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. Am J Hum Genet 83: 616-622.    
  • 118. Alvarado DM, McCall K, Aferol H, et al. (2011) Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Hum Mol Genet 20: 3943-3952.    
  • 119. Yong BC, Xun FX, Zhao LJ, et al. (2016) A systematic review of association studies of common variants associated with idiopathic congenital talipes equinovarus (ICTEV) in humans in the past 30 years. Springerplus 5: 896-016-2353-8. eCollection 2016.    
  • 120. Rodriguez-Esteban C, Tsukui T, Yonei S, et al. (1999) The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature 398: 814-818.    
  • 121. Alvarado DM, Aferol H, McCall K, et al. (2010) Familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4. Am J Hum Genet 87: 154-160.
  • 122. Lu W, Bacino CA, Richards BS, et al. (2012) Studies of TBX4 and chromosome 17q23.1q23.2: an uncommon cause of nonsyndromic clubfoot. Am J Med Genet A 158A: 1620-1627.
  • 123. Alnemri ES, Livingston DJ, Nicholson DW, et al. (1996) Human ICE/CED-3 protease nomenclature. Cell 87: 171.    
  • 124. Heck AL, Bray MS, Scott A, et al. (2005) Variation in CASP10 gene is associated with idiopathic talipes equinovarus. J Pediatr Orthop 25: 598-602.    
  • 125. Ester AR, Tyerman G, Wise CA, et al. (2007) Apoptotic gene analysis in idiopathic talipes equinovarus (clubfoot). Clin Orthop Relat Res 462: 32-37.    
  • 126. Daher S, Guimaraes AJ, Mattar R, et al. (2008) Bcl-2 and Bax expressions in pre-term, term and post-term placentas. Am J Reprod Immunol 60: 172-178.    
  • 127. Peebles DM (2004) Fetal consequences of chronic substrate deprivation. Semin Fetal Neonatal Med 9: 379-386.    
  • 128. Sundberg K, Bang J, Smidt-Jensen S, et al. (1997) Randomised study of risk of fetal loss related to early amniocentesis versus chorionic villus sampling. Lancet 350: 697-703.    
  • 129. Cederholm M, Haglund B, Axelsson O (2005) Infant morbidity following amniocentesis and chorionic villus sampling for prenatal karyotyping. BJOG 112: 394-402.    
  • 130. Mark M, Rijli FM, Chambon P (1997) Homeobox genes in embryogenesis and pathogenesis. Pediatr Res 42: 421-429.    
  • 131. McGinnis W, Krumlauf R (1992) Homeobox genes and axial patterning. Cell 68: 283-302.    
  • 132. Dobbs MB, Gurnett CA, Pierce B, et al. (2006) HOXD10 M319K mutation in a family with isolated congenital vertical talus. J Orthop Res 24: 448-453.    
  • 133. Shrimpton AE, Levinsohn EM, Yozawitz JM, et al. (2004) A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease. Am J Hum Genet 75: 92-96.    
  • 134. Weymouth KS, Blanton SH, Bamshad MJ, et al. (2011) Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot. Am J Med Genet A 155A: 2170-2179.
  • 135. McKillop DF, Geeves MA (1993) Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament. Biophys J 65: 693-701.    
  • 136. Gordon AM, Homsher E, Regnier M (2000) Regulation of contraction in striated muscle. Physiol Rev 80: 853-924.
  • 137. Weymouth KS, Blanton SH, Powell T, et al. (2016) Functional Assessment of Clubfoot Associated HOXA9, TPM1, and TPM2 Variants Suggests a Potential Gene Regulation Mechanism. Clin Orthop Relat Res 474: 1726-1735.    
  • 138. Castaneda C, Nalley K, Mannion C, et al. (2015) Clinical decision support systems for improving diagnostic accuracy and achieving precision medicine. J Clin Bioinforma 5: 4-015-0019-3. eCollection 2015.    
  • 139. Rehm HL (2013) Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet 14: 295-300.    
  • 140. Richards S, Aziz N, Bale S, et al. (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17: 405-424.    
  • 141. Green RC, Berg JS, Grody WW, et al. (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15: 565-574.    


Reader Comments

your name: *   your email: *  

Copyright Info: 2017, Neha Sinha, et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved