Skip to main content
SpringerLink
Log in

The Genetics Contributing to Disorders Involving Congenital Scoliosis

  • Chapter
  • First Online:
The Genetics and Development of Scoliosis

  • 806 Accesses

Abstract

Congenital scoliosis (CS) is a congenital deformity of the spine, which can present as an isolated malformation, or part of a syndrome with other clinical features such as renal, cardiac, gastrointestinal, and limb malformations, etc. FGF, WNT, Notch, and TGFβ signaling pathway-associated genes have important roles in spine development. In this chapter, we highlight the embryologic basis of CS, including relevant genes associated with CS etiology. We review the genetic approaches used to understand molecular etiologies and pathogenic mechanisms for CS. Genes contributing to CS and associated vertebral malformation syndromes are also summarized.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Wynne-Davies R. Congenital vertebral anomalies: aetiology and relationship to spina bifida cystica. J Med Genet. 1975;12:280–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Brand MC. Examination of the newborn with congenital scoliosis: focus on the physical. Adv Neonatal Care. 2008;8:265–73. 274–5

    Article  PubMed  Google Scholar 

  3. Beals RK, Robbins JR, Rolfe B. Anomalies associated with vertebral malformations. Spine (Phila Pa 1976). 1993;18:1329–32.

    Article  CAS  Google Scholar 

  4. Basu PS, Elsebaie H, Noordeen MH. Congenital spinal deformity: a comprehensive assessment at presentation. Spine (Phila Pa 1976). 2002;27:2255–9.

    Article  Google Scholar 

  5. Shen J, Wang Z, Liu J, et al. Abnormalities associated with congenital scoliosis: a retrospective study of 226 chinese surgical cases. Spine (Phila Pa 1976). 2013;38:814–8.

    Article  Google Scholar 

  6. Hensinger RN. Congenital scoliosis: etiology and associations. Spine (Phila Pa 1976). 2009;34:1745–50.

    Article  Google Scholar 

  7. Marks DS, Qaimkhani SA. The natural history of congenital scoliosis and kyphosis. Spine (Phila Pa 1976). 2009;34:1751–5.

    Article  Google Scholar 

  8. Cahill PJ, Samdani AF. Early-onset scoliosis. Orthopedics. 2012;35:1001–3.

    Article  PubMed  Google Scholar 

  9. Kamerlink JR, Quirno M, Auerbach JD, et al. Hospital cost analysis of adolescent idiopathic scoliosis correction surgery in 125 consecutive cases. J Bone Joint Surg Am. 2010;92:1097–104.

    Article  PubMed  Google Scholar 

  10. Giampietro PF, Raggio CL, Blank RD, et al. Clinical, genetic and environmental factors associated with congenital vertebral malformations. Mol Syndromol. 2013;4:94–105.

    PubMed  CAS  Google Scholar 

  11. Sparrow DB, Chapman G, Smith AJ, et al. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell. 2012;149:295–306.

    Article  PubMed  CAS  Google Scholar 

  12. Baker RE, Schnell S, Maini PK. A clock and wavefront mechanism for somite formation. Dev Biol. 2006;293:116–26.

    Article  PubMed  CAS  Google Scholar 

  13. Dequeant ML, Pourquie O. Segmental patterning of the vertebrate embryonic axis. Nat Rev Genet. 2008;9:370–82.

    Article  PubMed  CAS  Google Scholar 

  14. Palmeirim I, Henrique D, Ish-Horowicz D, et al. Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell. 1997;91:639–48.

    Article  PubMed  CAS  Google Scholar 

  15. Dequeant ML, Glynn E, Gaudenz K, et al. A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science. 2006;314:1595–8.

    Article  PubMed  CAS  Google Scholar 

  16. Dubrulle J, McGrew MJ, Pourquie O. FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell. 2001;106:219–32.

    Article  PubMed  CAS  Google Scholar 

  17. Hubaud A, Pourquie O. Signalling dynamics in vertebrate segmentation. Nat Rev Mol Cell Biol. 2014;15:709–21.

    Article  PubMed  CAS  Google Scholar 

  18. Takahashi Y, Koizumi K, Takagi A, et al. Mesp2 initiates somite segmentation through the Notch signalling pathway. Nat Genet. 2000;25:390–6.

    Article  PubMed  CAS  Google Scholar 

  19. Zhao W, Ajima R, Ninomiya Y, et al. Segmental border is defined by Ripply2-mediated Tbx6 repression independent of Mesp2. Dev Biol. 2015;400:105–17.

    Article  PubMed  CAS  Google Scholar 

  20. Kitajima S, Takagi A, Inoue T, et al. MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development. 2000;127:3215–26.

    PubMed  CAS  Google Scholar 

  21. Chen W, Liu J, Yuan D, et al. Progress and perspective of TBX6 gene in congenital vertebral malformations. Oncotarget. 2016;7:57430–41.

    PubMed  PubMed Central  Google Scholar 

  22. Vermot J, Gallego LJ, Fraulob V, et al. Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo. Science. 2005;308:563–6.

    Article  PubMed  CAS  Google Scholar 

  23. Vermot J, Pourquie O. Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos. Nature. 2005;435:215–20.

    Article  PubMed  CAS  Google Scholar 

  24. Kawakami Y, Raya A, Raya RM, et al. Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature. 2005;435:165–71.

    Article  PubMed  CAS  Google Scholar 

  25. McInerney-Leo AM, Sparrow DB, Harris JE, et al. Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Hum Mol Genet. 2014;24:1234–42.

    Article  PubMed  CAS  Google Scholar 

  26. Dias AS, de Almeida I, Belmonte JM, et al. Somites without a clock. Science. 2014;343:791–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Giampietro PF, Raggio CL, Reynolds CE, et al. An analysis of PAX1 in the development of vertebral malformations. Clin Genet. 2005;68:448–53.

    Article  PubMed  CAS  Google Scholar 

  28. Tassabehji M, Fang ZM, Hilton EN, et al. Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Hum Mutat. 2008;29:1017–27.

    Article  PubMed  CAS  Google Scholar 

  29. Wu N, Ming X, Xiao J, et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med. 2015;372:341–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Ye M, Berry-Wynne KM, Asai-Coakwell M, et al. Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Hum Mol Genet. 2010;19:287–98.

    Article  PubMed  CAS  Google Scholar 

  31. Bayrakli F, Guclu B, Yakicier C, et al. Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype. BMC Genet. 2013;14:95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Giampietro PF, Armstrong L, Stoddard A, et al. Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes. Am J Med Genet A. 2015;167A:95–102.

    Article  PubMed  CAS  Google Scholar 

  33. Fukushima Y, Ohashi H, Wakui K, et al. De novo apparently balanced reciprocal translocation between 5q11.2 and 17q23 associated with Klippel-Feil anomaly and type A1 brachydactyly. Am J Med Genet. 1995;57:447–9.

    Article  PubMed  CAS  Google Scholar 

  34. Papagrigorakis MJ, Synodinos PN, Daliouris CP, et al. De novo inv(2)(p12q34) associated with Klippel-Feil anomaly and hypodontia. Eur J Pediatr. 2003;162:594–7.

    Article  PubMed  Google Scholar 

  35. Goto M, Nishimura G, Nagai T, et al. Familial Klippel-Feil anomaly and t(5;8)(q35.1;p21.1) translocation. Am J Med Genet A. 2006;140:1013–5.

    Article  PubMed  Google Scholar 

  36. Giampietro PF, Blank RD, Raggio CL, et al. Congenital and idiopathic scoliosis: clinical and genetic aspects. Clin Med Res. 2003;1:125–36.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Giampietro PF, Raggio CL, Blank RD. Synteny-defined candidate genes for congenital and idiopathic scoliosis. Am J Med Genet. 1999;83:164–77.

    Article  PubMed  CAS  Google Scholar 

  38. Ghebranious N, Blank RD, Raggio CL, et al. A missense T (Brachyury) mutation contributes to vertebral malformations. J Bone Miner Res. 2008;23:1576–83.

    Article  PubMed  CAS  Google Scholar 

  39. Ghebranious N, Raggio CL, Blank RD, et al. Lack of evidence of WNT3A as a candidate gene for congenital vertebral malformations. Scoliosis. 2007;2:13.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Giampietro PF, Raggio CL, Reynolds C, et al. DLL3 as a candidate gene for vertebral malformations. Am J Med Genet A. 2006;140:2447–53.

    Article  PubMed  CAS  Google Scholar 

  41. Ghebranious N, Burmester JK, Glurich I, et al. Evaluation of SLC35A3 as a candidate gene for human vertebral malformations. Am J Med Genet A. 2006;140:1346–8.

    Article  PubMed  CAS  Google Scholar 

  42. Wu N, Yuan S, Liu J, et al. Association of LMX1A genetic polymorphisms with susceptibility to congenital scoliosis in Chinese Han population. Spine (Phila Pa 1976). 2014;39:1785–91.

    Article  Google Scholar 

  43. Windpassinger C, Piard J, Bonnard C, et al. CDK10 mutations in humans and mice cause severe growth retardation, spine malformations, and developmental delays. Am J Hum Genet. 2017;101:391–403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Thomsen B, Horn P, Panitz F, et al. A missense mutation in the bovine SLC35A3 gene, encoding a UDP-N-acetylglucosamine transporter, causes complex vertebral malformation. Genome Res. 2006;16:97–105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Duncan RJ, Carrig CB, Agerholm JS, et al. Complex vertebral malformation in a Holstein calf: report of a case in the USA. J Vet Diagn Investig. 2001;13:333–6.

    Article  Google Scholar 

  46. Edmondson AC, Bedoukian EC, Deardorff MA, et al. A human case of SLC35A3-related skeletal dysplasia. Am J Med Genet A. 2017;173:2758–62.

    Article  PubMed  CAS  Google Scholar 

  47. Fei Q, Wu Z, Wang H, et al. The association analysis of TBX6 polymorphism with susceptibility to congenital scoliosis in a Chinese Han population. Spine (Phila Pa 1976). 2010;35:983–8.

    Article  Google Scholar 

  48. Papapetrou C, Putt W, Fox M, et al. The human TBX6 gene: cloning and assignment to chromosome 16p11.2. Genomics. 1999;55:238–41.

    Article  PubMed  CAS  Google Scholar 

  49. Hubaud A, Pourquié O. Signalling dynamics in vertebrate segmentation. Nat Rev Mol Cell Biol. 2014;15:709–21.

    Article  PubMed  CAS  Google Scholar 

  50. Aulehla A, Wehrle C, Brand-Saberi B, et al. Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev Cell. 2003;4:395–406.

    Article  PubMed  CAS  Google Scholar 

  51. White PH, Chapman DL. Dll1 is a downstream target of Tbx6 in the paraxial mesoderm. Genesis. 2005;42:193–202.

    Article  PubMed  CAS  Google Scholar 

  52. Chapman DL, Papaioannou VE. Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature. 1998;391:695–7.

    Article  PubMed  CAS  Google Scholar 

  53. Hirata H, Bessho Y, Kokubu H, et al. Instability of Hes7 protein is crucial for the somite segmentation clock. Nat Genet. 2004;36:750–4.

    Article  PubMed  CAS  Google Scholar 

  54. Shimojima K, Inoue T, Fujii Y, et al. A familial 593-kb microdeletion of 16p11.2 associated with mental retardation and hemivertebrae. Eur J Med Genet. 2009;52:433–5.

    Article  PubMed  Google Scholar 

  55. Al-Kateb H, Khanna G, Filges I, et al. Scoliosis and vertebral anomalies: additional abnormal phenotypes associated with chromosome 16p11.2 rearrangement. Am J Med Genet A. 2014;164A:1118–26.

    Article  PubMed  CAS  Google Scholar 

  56. Takeda K, Kou I, Kawakami N, et al. Compound heterozygosity for null mutations and a common hypomorphic risk haplotype in TBX6 causes congenital scoliosis. Hum Mutat. 2017;38:317–23.

    Article  PubMed  CAS  Google Scholar 

  57. Lefebvre M, Duffourd Y, Jouan T, et al. Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis. Clin Genet. 2017;91:908–12.

    Article  PubMed  CAS  Google Scholar 

  58. Offiah A, Alman B, Cornier AS, et al. Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae. Am J Med Genet A. 2010;152A:1357–71. n/a-n/a

    PubMed  Google Scholar 

  59. Bulman MP, Kusumi K, Frayling TM, et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet. 2000;24:438–41.

    Article  PubMed  CAS  Google Scholar 

  60. Whittock NV, Sparrow DB, Wouters MA, et al. Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet. 2004;74:1249–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Sparrow DB, Chapman G, Wouters MA, et al. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet. 2006;78:28–37.

    Article  PubMed  CAS  Google Scholar 

  62. Sparrow DB, Guillen-Navarro E, Fatkin D, et al. Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis. Hum Mol Genet. 2008;17:3761–6.

    Article  PubMed  CAS  Google Scholar 

  63. Sparrow DB, McInerney-Leo A, Gucev ZS, et al. Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Hum Mol Genet. 2013;22:1625–31.

    Article  PubMed  CAS  Google Scholar 

  64. Clarke RA, Singh S, McKenzie H, et al. Familial Klippel-Feil syndrome and paracentric inversion inv(8)(q22.2q23.3). Am J Hum Genet. 1995;57:1364–70.

    PubMed  PubMed Central  CAS  Google Scholar 

  65. Mohamed JY, Faqeih E, Alsiddiky A, et al. Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly. Am J Hum Genet. 2013;92:157–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Malfatti E, Bohm J, Lacene E, et al. A premature stop codon in MYO18B is associated with severe nemaline myopathy with cardiomyopathy. J Neuromuscul Dis. 2015;2:219–27.

    Article  PubMed  PubMed Central  Google Scholar 

  67. McGaughran JM, Oates A, Donnai D, et al. Mutations in PAX1 may be associated with Klippel-Feil syndrome. Eur J Hum Genet. 2003;11:468–74.

    Article  PubMed  CAS  Google Scholar 

  68. Karaca E, Yuregir OO, Bozdogan ST, et al. Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome. Am J Med Genet A. 2015;167:2795–9.

    Article  CAS  Google Scholar 

  69. Vozzi D, Licastro D, Martelossi S, et al. Alagille syndrome: a new missense mutation detected by whole-exome sequencing in a case previously found to be negative by DHPLC and MLPA. Mol Syndromol. 2013;4:207–10.

    PubMed  PubMed Central  CAS  Google Scholar 

  70. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the NOTCH signaling pathway. Am J Hum Genet. 2006;79:169–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Wessels MW, Kuchinka B, Heydanus R, et al. Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder? J Med Genet. 2010;47:351–5.

    Article  PubMed  CAS  Google Scholar 

  72. Hilger AC, Halbritter J, Pennimpede T, et al. Targeted Resequencing of 29 candidate genes and mouse expression studies implicate ZIC3 and FOXF1 in human VATER/VACTERL Association. Hum Mutat. 2015;36:1150–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Chung B, Shaffer LG, Keating S, et al. From VACTERL-H to heterotaxy: variable expressivity of ZIC3-related disorders. Am J Med Genet A. 2011;155A:1123–8.

    Article  PubMed  CAS  Google Scholar 

  74. Saisawat P, Kohl S, Hilger AC, et al. Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney Int. 2014;85:1310–7.

    Article  PubMed  CAS  Google Scholar 

  75. Nakamura Y, Kikugawa S, Seki S, et al. PCSK5 mutation in a patient with the VACTERL association. BMC Res Notes. 2015;8:228.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Stankiewicz P, Sen P, Bhatt SS, et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009;84:780–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Shi H, Enriquez A, Rapadas M, et al. NAD deficiency, congenital malformations, and niacin supplementation. N Engl J Med. 2017;377:544–52.

    Article  PubMed  CAS  Google Scholar 

  78. Keegan CE, Mulliken JB, Wu BL, et al. Townes-Brocks syndrome versus expanded spectrum hemifacial microsomia: review of eight patients and further evidence of a “hot spot” for mutation in the SALL1 gene. Genet Med. 2001;3:310–3.

    Article  PubMed  CAS  Google Scholar 

  79. Fischer S, Ludecke HJ, Wieczorek D, et al. Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum. Hum Mol Genet. 2006;15:581–7.

    Article  PubMed  CAS  Google Scholar 

  80. Lopez E, Berenguer M, Tingaud-Sequeira A, et al. Mutations in MYT1, encoding the myelin transcription factor 1, are a rare cause of OAVS. J Med Genet. 2016;53:752–60.

    Article  PubMed  CAS  Google Scholar 

  81. Gucev ZS, Tasic V, Pop-Jordanova N, et al. Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: negative mutation analysis of DLL3, MESP2, HES7, and LFNG. Am J Med Genet A. 2010;152A:1378–82.

    PubMed  Google Scholar 

  82. Saker E, Loukas M, Oskouian RJ, et al. The intriguing history of vertebral fusion anomalies: the Klippel-Feil syndrome. Childs Nerv Syst. 2016;32:1599–602.

    Article  PubMed  Google Scholar 

  83. Tracy MR, Dormans JP, Kusumi K. Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin Orthop Relat Res. 2004;424:183–90.

    Article  Google Scholar 

  84. Samartzis DD, Herman J, Lubicky JP, et al. Classification of congenitally fused cervical patterns in Klippel-Feil patients: epidemiology and role in the development of cervical spine-related symptoms. Spine (Phila Pa 1976). 2006;31:E798–804.

    Article  Google Scholar 

  85. Alazami AM, Kentab AY, Faqeih E, et al. A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B. J Med Genet. 2015;52:400–4.

    Article  PubMed  CAS  Google Scholar 

  86. Skuntz S, Mankoo B, Nguyen MT, et al. Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton. Dev Biol. 2009;332:383–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Rodrigo I, Bovolenta P, Mankoo BS, et al. Meox homeodomain proteins are required for Bapx1 expression in the sclerotome and activate its transcription by direct binding to its promoter. Mol Cell Biol. 2004;24:2757–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Ajima R, Akazawa H, Kodama M, et al. Deficiency of Myo18B in mice results in embryonic lethality with cardiac myofibrillar aberrations. Genes Cells. 2008;13:987–99.

    Article  PubMed  CAS  Google Scholar 

  89. Dietrich S, Schubert FR, Gruss P. Altered Pax gene expression in murine notochord mutants: the notochord is required to initiate and maintain ventral identity in the somite. Mech Dev. 1993;44:189–207.

    Article  PubMed  CAS  Google Scholar 

  90. Dietrich S, Schubert FR, Lumsden A. Control of dorsoventral pattern in the chick paraxial mesoderm. Development. 1997;124:3895–908.

    PubMed  CAS  Google Scholar 

  91. Dietrich S, Gruss P. Undulated phenotypes suggest a role of Pax-1 for the development of vertebral and extravertebral structures. Dev Biol. 1995;167:529–48.

    Article  PubMed  CAS  Google Scholar 

  92. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20:251–7.

    Article  PubMed  CAS  Google Scholar 

  93. Laufer-Cahana A, Krantz ID, Bason LD, et al. Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion. Am J Med Genet. 2002;112:190–3.

    Article  PubMed  Google Scholar 

  94. Giannakudis J, Ropke A, Kujat A, et al. Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet. 2001;9:209–16.

    Article  PubMed  CAS  Google Scholar 

  95. Munoz-Aguilar G, Domingo-Triado I, Maravall-Llagaria M, et al. Previously undescribed family mutation in the JAG1 gene as a cause for Alagille syndrome. J Pediatr Gastroenterol Nutr. 2017;64:e135–6.

    Article  PubMed  CAS  Google Scholar 

  96. Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75–82.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Tsai EA, Gilbert MA, Grochowski CM, et al. THBS2 is a candidate modifier of liver disease severity in Alagille syndrome. Cell Mol Gastroenterol Hepatol. 2016;2:663–75.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Khoury MJ, Cordero JF, Greenberg F, et al. A population study of the VACTERL association: evidence for its etiologic heterogeneity. Pediatrics. 1983;71:815–20.

    PubMed  CAS  Google Scholar 

  99. Solomon BD, Pineda-Alvarez DE, Raam MS, et al. Analysis of component findings in 79 patients diagnosed with VACTERL association. Am J Med Genet A. 2010;152A:2236–44.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Chen Y, Liu Z, Chen J, et al. The genetic landscape and clinical implications of vertebral anomalies in VACTERL association. J Med Genet. 2016;53(7):431.

    Article  PubMed  CAS  Google Scholar 

  101. Dworschak GC, Draaken M, Marcelis C, et al. De novo 13q deletions in two patients with mild anorectal malformations as part of VATER/VACTERL and VATER/VACTERL-like association and analysis of EFNB2 in patients with anorectal malformations. Am J Med Genet A. 2013;161A:3035–41.

    Article  PubMed  CAS  Google Scholar 

  102. Peddibhotla S, Khalifa M, Probst FJ, et al. Expanding the genotype-phenotype correlation in subtelomeric 19p13.3 microdeletions using high resolution clinical chromosomal microarray analysis. Am J Med Genet A. 2013;161A:2953–63.

    Article  PubMed  CAS  Google Scholar 

  103. Touliatou V, Fryssira H, Mavrou A, et al. Clinical manifestations in 17 Greek patients with Goldenhar syndrome. Genet Couns. 2006;17:359–70.

    PubMed  CAS  Google Scholar 

  104. Amalnath SD, Subrahmanyam DK, Dutta TK, et al. Familial oculoauriculovertebral sequence with lymphoma in one sibling. Am J Med Genet A. 2008;146A:3082–5.

    Article  PubMed  Google Scholar 

  105. Slavotinek AM, Vargervik K. Expanded spectrum of oculo-auriculo-vertebral spectrum with imperforate anus in a male patient who is negative for SALL1 mutations. Clin Dysmorphol. 2011;20:11–4.

    Article  PubMed  Google Scholar 

  106. Kosaki R, Fujimaru R, Samejima H, et al. Wide phenotypic variations within a family with SALL1 mutations: isolated external ear abnormalities to Goldenhar syndrome. Am J Med Genet A. 2007;143A:1087–90.

    Article  PubMed  CAS  Google Scholar 

  107. Zielinski D, Markus B, Sheikh M, et al. OTX2 duplication is implicated in hemifacial microsomia. PLoS One. 2014;9:e96788.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Beleza-Meireles A, Hart R, Clayton-Smith J, et al. Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients. Eur J Med Genet. 2015;58:455–65.

    Article  PubMed  Google Scholar 

  109. Stray-Pedersen A, Sorte HS, Samarakoon P, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 2017;139:232–45.

    Article  PubMed  Google Scholar 

  110. Posey JE, Harel T, Liu P, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376:21–31.

    Article  PubMed  CAS  Google Scholar 

  111. Zheng HF, Forgetta V, Hsu YH, et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015;526:112–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    Nan Wu

  2. Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China

    Nan Wu

  3. Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China

    Nan Wu

  4. Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA

    Philip Giampietro

  5. Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan

    Kazuki Takeda

  6. Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan

    Kazuki Takeda

Authors
  1. Nan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip Giampietro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazuki Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nan Wu .

Editor information

Editors and Affiliations

  1. School of Life Sciences, Arizona State University, Tempe, Arizona, USA

    Kenro Kusumi

  2. Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, Australia

    Sally L. Dunwoodie

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wu, N., Giampietro, P., Takeda, K. (2018). The Genetics Contributing to Disorders Involving Congenital Scoliosis. In: Kusumi, K., Dunwoodie, S. (eds) The Genetics and Development of Scoliosis. Springer, Cham. https://doi.org/10.1007/978-3-319-90149-7_4

Download citation

Publish with us

Policies and ethics

Search

Navigation