Skip to main content

Advertisement

SpringerLink
Log in

Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis

  • Genetics
  • Published:
Spine Deformity Aims and scope Submit manuscript

Abstract

Study Design

To test for rare genetic mutations, a cohort of patients with unexplained early-onset scoliosis (EOS) was screened using high-density microarray genotyping. A cohort of patients with adolescent idiopathic scoliosis (AIS) was similarly screened and the results were compared.

Summary of Background Data

Patients with scoliosis in infancy or early childhood (EOS) are at high risk for progressive deformity and associated problems including respiratory compromise. Early-onset scoliosis is frequently associated with genetic disorders but many patients present with nonspecific clinical features and without an associated diagnosis. The authors hypothesized that EOS in these patients may be caused by rare genetic mutations detectable by next-generation genomic methods.

Methods

The researchers identified 24 patients with unexplained EOS from pediatric orthopedic clinics. They genotyped them, along with 39 connecting family members, using the Illumina OmniExpress-12, version 1.0 beadchip. Resulting genotypes were analyzed for chro¬mosomal changes, specifically copy number variation and absence of heterozygosity. They screened 482 adolescent idiopathic scoliosis (AIS) patients and 744 healthy controls, who were similarly genotyped with the same beadchip, for chromosomal changes identified in the EOS cohort.

Results

Copy number variation and absence of heterozygosity analyses revealed a genetic diagnosis of chromosome 15q24 microdeletion syndrome in 1 patient and maternal uniparental disomy of chromosome 14 in a second one. Prior genetic testing and clinical evaluations had been negative in both cases. A large novel chromosome 10 deletion was likely causal in a third EOS patient. These mutations identified in the EOS patients were absent in AIS patients and controls, and thus were not associated with AIS or found in asymptomatic individuals.

Conclusions

These data underscore the usefulness of updated genetic evaluations including high-density microarray-based genotyping and other next-generation methods in patients with unexplained EOS, even when prior genetic studies were negative. These data also suggest the intriguing possibility that other mutations detectable by whole genome sequencing, as well as epigenetic effects, await dis¬covery in the EOS population.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Phillips JH, Knapp Jr DR, Herrera-Soto J. Mortality and morbidity in early-onset scoliosis surgery. Spine (Phila Pa 1976) 2013;38:324–7.

    Article  Google Scholar 

  2. Mortality rate, under-5 (per 1,000 live births). http://data.worldbank.org/indicator/SH.DYN.MORT. Accessed January 30, 2013.

  3. Herring JA. Tachdjian’s pediatric orthopaedics. Philadelphia, PA: WB Saunders; 2008.

    Google Scholar 

  4. Karol LA. Early definitive spinal fusion in young children: what we have learned. Clin Orthop Relat Res 2011;469:1323–9.

    Article  Google Scholar 

  5. Campbell RM. VEPTR expansion thoracoplasty. In: Akbarnia BA, Yazici M, Thompson GH, editors. The growing spine: management of spinal disorders in young children. New York, NY: Springer-Verlag; 2011. p. 469–86.

    Chapter  Google Scholar 

  6. Akbarnia BA, Mundis Jr GM, Salari P, et al. Dual growing rods. In: Akbarnia BA, Yazici M, Thompson GH, editors. The growing spine: management of spinal disorders in young children. New York, NY: Springer-Verlag; 2010. p. 449-68.

    Chapter  Google Scholar 

  7. Son-Hing GHTJP, Akbarnia BA, Thompson GH, et al. Single growing rods. In: Akbarnia BA, Yazici M, Thompson GH, editors. The growing spine: management of spinal disorders in young children. New York, NY: Springer-Verlag; 2010. p. 441–8.

    Google Scholar 

  8. 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  CAS  Google Scholar 

  9. Herring J, editor. Tachdjian’s pediatric orthopaedics, Vol. 1. Philadelphia, PA: WB Saunders; 2008.

  10. Akbarnia BA. Management themes in early onset scoliosis. J Bone Joint Surg Am 2007;89(suppl 1):42–54.

    Article  Google Scholar 

  11. Wynne-Davies R. Infantile idiopathic scoliosis: causative factors, particularly in the first Six months of life. J Bone Joint Surg Br 1975;57:138–41.

    Article  CAS  Google Scholar 

  12. Paria N, Copley LA, Herring JA, et al. The impact of large-scale genomic methods in orthopaedic disorders: insights from genome-wide association studies. J Bone J Surg Am 2014;96(38):1–10.

    Google Scholar 

  13. Slavotinek AM. Novel microdeletion syndromes detected by chromosome microarrays. J Hum Genet 2008;124:1–17.

    Article  CAS  Google Scholar 

  14. Jiang Y, Tsai TF, Bressler J, Beaudet AL. Imprinting in Angelman and Prader-Willi syndromes. Curr Opin Genet Dev 1998;8:334–42.

    Article  CAS  Google Scholar 

  15. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010;86:749–64.

    Article  CAS  Google Scholar 

  16. McQuillan R, Leutenegger AL, Abdel-Rahman R, et al. Runs of homozygosity in European populations. Am J Hum Genet 2008;83:359–72.

    Article  CAS  Google Scholar 

  17. Cushman LJ, Torres-Martinez W, Cherry AM, et al. A report of three patients with an interstitial deletion of chromosome 15q24. Am J Med Genet A 2005;137:65–71.

    Article  Google Scholar 

  18. Temple IK, Cockwell A, Hassold T, et al. Maternal uniparental disomy for chromosome 14. J Med Genet 1991;28:511–4.

    Article  CAS  Google Scholar 

  19. Temple IK, Shrubb V, Lever M, et al. Isolated imprinting mutation of the DLK1/GTL2 locus associated with a clinical presentation of maternal uniparental disomy of chromosome 14. J Med Genet 2007;44:637–40.

    Article  CAS  Google Scholar 

  20. Kagami M, Sekita Y, Nishimura G, et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet 2008;40:237–42.

    Article  CAS  Google Scholar 

  21. Hosoki K, Kagami M, Tanaka T, et al. Maternal uniparental disomy 14 syndrome demonstrates Prader-Willi syndrome-like phenotype. J. Pediatr 2009;155:900–3.

    Article  CAS  Google Scholar 

  22. Jen JC, Chan WM, Bosley TM, et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 2004;304:1509–13.

    Article  CAS  Google Scholar 

  23. Sharp AJ, Selzer RR, Veltman JA, et al. Characterization of a recurrent 15q24 microdeletion syndrome. Hum Mol Genet 2007;16:567–72.

    Article  CAS  Google Scholar 

  24. Klopocki E, Graul-Neumann LM, Grieben U, et al. A further case of the recurrent 15q24 microdeletion syndrome, detected by array CGH. Eur J Pediatr 2008;167:903–8.

    Article  Google Scholar 

  25. El-Hattab AW, Smolarek TA, Walker ME, et al. Redefined genomic architecture in 15q24 directed by patient deletion/duplication break-point mapping. Hum Genet 2009;126:589–602.

    Article  Google Scholar 

  26. Masurel-Paulet A, Callier P, Thauvin-Robinet C, et al. Multiple cysts of the corpus callosum and psychomotor delay in a patient with a 3.1 Mb 15q24.1q24.2 interstitial deletion identified by array-CGH. Am J Med Genet A 2009;149:1504–10.

    Article  Google Scholar 

  27. Van Esch H, Backx L, Pijkels E, et al. Congenital diaphragmatic hernia is part of the new 15q24 microdeletion syndrome. Eur J Med Genet 2009;52:153–6.

    Article  Google Scholar 

  28. Andrieux J, Dubourg C, Rio M, et al. Genotype-phenotype correlation in four 15q24 deleted patients identified by array-CGH. Am J Med Genet A 2009;149:2813–9.

    Article  Google Scholar 

  29. Sharma S, Gao X, Londono D, et al. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet 2011;20:1456–66.

    Article  CAS  Google Scholar 

  30. Takahashi Y, Kou I, Takahashi A, et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet 2011;43:1237–40.

    Article  CAS  Google Scholar 

  31. Ogata T, Kagami M, Ferguson-Smith AC. Molecular mechanisms regulating phenotypic outcome in paternal and maternal uniparental disomy for chromosome 14. Epigenetics 2008;3:181–7.

    Article  Google Scholar 

  32. Bagri A, Marin O, Plump AS, et al. Slit proteins prevent midline crossing and determine the dorsoventral position of major axonal pathways in the mammalian forebrain. Neuron 2002;33:233–48.

    Article  CAS  Google Scholar 

  33. Marillat V, Sabatier C, Failli V, et al. The slit receptor Rig-1/Robo3 controls midline crossing by hindbrain precerebellar neurons and axons. Neuron 2004;43:69–79.

    Article  CAS  Google Scholar 

  34. Shashi V, McConkie-Rosell A, Rosell B, et al. The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet Med 2014;16:176–82.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 2222 Welborn St., Dallas, TX, 75219, USA

    Xiaochong Gao MS, MD & Carol A. Wise phD

  2. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Garrett Gotway MD & Carol A. Wise phD

  3. Department of Orthopedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, TX, USA

    Karl Rathjen MD & Charles Johnston MD

  4. Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas, 75390, USA

    Karl Rathjen MD, Charles Johnston MD & Carol A. Wise phD

  5. Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, TX, USA

    Steven Sparagana MD

  6. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Steven Sparagana MD

  7. McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas, 75390, USA

    Carol A. Wise phD

Authors
  1. Xiaochong Gao MS, MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Garrett Gotway MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karl Rathjen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles Johnston MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven Sparagana MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carol A. Wise phD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carol A. Wise phD.

Additional information

Author disclosures: XG (none); GG (none); KR (grant from Fondation Cotrel); CJ (personal fees from Medtronic; patents); SS (none); CAW (none).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, X., Gotway, G., Rathjen, K. et al. Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis. Spine Deform 2, 324–332 (2014). https://doi.org/10.1016/j.jspd.2014.04.014

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.jspd.2014.04.014

Keywords

Search

Navigation