The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP).


Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis.


A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%).


NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Senior co-authors:Helly Goez and Clara D. van Karnebeek.


  1. 1.

    Rosenbaum P, Paneth N, Leviton A, et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl. 2007;109:8–14.

  2. 2.

    Aisen ML, Kerkovich D, Mast J, et al. Cerebral palsy: clinical care and neurological rehabilitation. Lancet Neurol. 2011;10:844–852.

  3. 3.

    Mac Keith RC, Keith RCM, Polani PE, Lipmann K, Wheeler DE, Shepherd IDD. Cerebral palsy. Lancet. 1958;271:961–962.

  4. 4.

    Bax MCO. Terminology and classification of cerebral palsy. Dev Med Child Neurol. 1964;6:295–297.

  5. 5.

    World Health Organization. International Classification of Functioning, Disability and Health: ICF. World Health Organization; 2001.

  6. 6.

    Oskoui M, Coutinho F, Dykeman J, Jetté N, Pringsheim T. An update on the prevalence of cerebral palsy: a systematic review and meta-analysis. Dev Med Child Neurol. 2013;55:509–519.

  7. 7.

    Moreno-De-Luca A, Andres M-D-L, Ledbetter DH, Martin CL. Genetic insights into the causes and classification of the cerebral palsies. Lancet Neurol. 2012;11:283–292.

  8. 8.

    Bax M, Goldstein M, Rosenbaum P, et al. Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol. 2005;47:571–576.

  9. 9.

    McMichael G, Bainbridge MN, Haan E, et al. Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy. Mol Psychiatry. 2015;20:176–182.

  10. 10.

    Leach EL, Shevell M, Bowden K, Stockler-Ipsiroglu S, van Karnebeek CDM. Treatable inborn errors of metabolism presenting as cerebral palsy mimics: systematic literature review. Orphanet J Rare Dis. 2014;9:197.

  11. 11.

    Boycott KM, Rath A, Chong JX, et al. International cooperation to enable the diagnosis of all rare genetic diseases. Am J Hum Genet. 2017;100:695–705.

  12. 12.

    Tarailo-Graovac M, Shyr C, Ross CJ, et al. Exome sequencing and the management of neurometabolic disorders. N Engl J Med. 2016;374:2246–2255.

  13. 13.

    Takezawa Y, Kikuchi A, Haginoya K, et al. Genomic analysis identifies masqueraders of full-term cerebral palsy. Ann Clin Transl Neurol. 2018;5:538–551.

  14. 14.

    Himmelmann K, Horber V, De La Cruz J, et al. MRI classification system (MRICS) for children with cerebral palsy: development, reliability, and recommendations. Dev Med Child Neurol. 2017;59:57–64.

  15. 15.

    Dunbar M, Jaggumantri S, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CDM. Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Mol Genet Metab. 2014;112:259–274.

  16. 16.

    De Ligt J, Willemsen MH, Van Bon BWM, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921–1929.

  17. 17.

    Matthews AM, Tarailo-Graovac M, Price EM, et al. A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder. Eur J Med Genet. 2017;60:548–552.

  18. 18.

    Richards S, Aziz N, Bale S, et al. 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. 2015;17:405–424.

  19. 19.

    Shen E, Shulha H, Weng Z, Akbarian S Regulation of histone H3K4 methylation in brain development and disease. Philos Trans R Soc Lond B Biol Sci 2014;369. Accessed 7 Dec. 2018.

  20. 20.

    Meyer E, Carss KJ, Rankin J, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2017;49:223–237.

  21. 21.

    Waak M, Mohammad SS, Coman D, et al. GNAO1-related movement disorder with life-threatening exacerbations: movement phenomenology and response to DBS. J Neurol Neurosurg Psychiatry. 2018;89:221–222.

  22. 22.

    Honey CM, Malhotra AK, Tarailo-Graovac M, van Karnebeek CDM, Horvath G, Sulistyanto A. GNAO1 mutation-induced pediatric dystonic storm rescue with pallidal deep brain stimulation. J Child Neurol. 2018;33:413–416.

  23. 23.

    Horvath GA, Tarailo-Graovac M, Bartel T, et al. Improvement of self-injury with dopamine and serotonin replacement therapy in a patient with a hemizygous PAK3 mutation: a new therapeutic strategy for neuropsychiatric features of an intellectual disability syndrome. J Child Neurol. 2018;33:106–113.

  24. 24.

    Rincón E, Gharbi SI, Santos-Mendoza T, Mérida I. Diacylglycerol kinase ζ: at the crossroads of lipid signaling and protein complex organization. Prog Lipid Res. 2012;51:1–10.

  25. 25.

    Ishisaka M, Hara H. The roles of diacylglycerol kinases in the central nervous system: review of genetic studies in mice. J Pharmacol Sci. 2014;124:336–343.

  26. 26.

    Flanagan JG, Vanderhaeghen P. The ephrins and Eph receptors in neural development. Annu Rev Neurosci. 1998;21:309–345.

  27. 27.

    Li C, Chen R, Fan X, et al. EPHA4 haploinsufficiency is responsible for the short stature of a patient with 2q35-q36.2 deletion and Waardenburg syndrome. BMC Med Genet. 2015;16:23.

  28. 28.

    Leighton PA, Mitchell KJ, Goodrich LV, et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature. 2001;410:174–179.

  29. 29.

    Kutzleb C, Sanders G, Yamamoto R, et al. Paralemmin, a prenyl-palmitoyl-anchored phosphoprotein abundant in neurons and implicated in plasma membrane dynamics and cell process formation. J Cell Biol. 1998;143:795–813.

  30. 30.

    Arstikaitis P, Gauthier-Campbell C, Carolina Gutierrez Herrera R, et al. Paralemmin-1, a modulator of filopodia induction is required for spine maturation. Mol Biol Cell. 2008;19:2026–2038.

  31. 31.

    Bortolato M, Floris G, Shih JC. From aggression to autism: new perspectives on the behavioral sequelae of monoamine oxidase deficiency. J Neural Transm (Vienna). 2018;125:1589–1599.

  32. 32.

    Yaron A, Huang P-H, Cheng H-J, Tessier-Lavigne M. Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins. Neuron. 2005;45:513–523.

  33. 33.

    Smith CL, Blake JA, Kadin JA, Richardson JE, Bult CJ, Mouse Genome Database Group. Mouse Genome Database (MGD)-2018: knowledgebase for the laboratory mouse. Nucleic Acids Res. 2017;46(D1):D836–D842.

  34. 34.

    MacLennan AH, Kruer MC, Baynam G, et al. Cerebral palsy and genomics: an international consortium. Dev Med Child Neurol. 2018;60:209–210.

  35. 35.

    Centers for Disease Control and Prevention (CDC). Economic costs associated with mental retardation, cerebral palsy, hearing loss, and vision impairment—United States, 2003. MMWR Morb Mortal Wkly Rep. 2004;53:57–59.

  36. 36.

    Srivastava S, Siddharth S, Cohen JS, et al. Clinical whole exome sequencing in child neurology practice. Ann Neurol. 2014;76:473–483.

  37. 37.

    van Karnebeek CDM, Wortmann SB, Tarailo-Graovac M, et al. The role of the clinician in the multi-omics era: are you ready? J Inherit Metab Dis. 2018;41:571–582.

  38. 38.

    Karaca E, Posey JE, Coban Akdemir Z, et al. Phenotypic expansion illuminates multilocus pathogenic variation. Genet Med. 2018 Apr 26; [Epub ahead of print].

  39. 39.

    Theunissen TEJ, Sallevelt SCEH, Hellebrekers DMEI, et al. Rapid resolution of blended or composite multigenic disease in infants by whole-exome sequencing. J Pediatr. 2017;182:371–374.e2.

Download references


We would like to thank the patients and families for participation in this study, and their local physicians and health care teams for providing us the medical reports. We are grateful to X. Han, F. Miao, and M. Higginson for DNA extraction, triplet repeat primed polymerase chain reaction (TP-PCR), and Sanger sequencing; and to E. Lomba, A. Ghani, L. Muttumacoroe, and D. Pak for patient enrollment, study administration, and logistic support.

This work was supported by funding from the B.C. Children’s Hospital Foundation (1st Collaborative Area of Innovation), Neurodevnet (Strategic Opportunity Fund to C.D.v.K., S.S.), Glenrose Rehabilitation Hospital Foundation, the Canadian Institutes of Health Research (grant number 301221), the National Ataxia Foundation, and the Rare Diseases Foundation. Informatics infrastructure was supported by Genome BC and Genome Canada (ABC4DE Project). C.D.v.K. and C.J.R. are recipients of the Michael Smith Foundation for Health Research Scholar Award. C.D.v.K. received a salary award from Stichting Metakids. A.M.M. received stipends from the BC Children’s Research Institute as postdoctoral fellow; B.D. received stipends from the Canadian Institutes of Health Research Drug Safety and Effectiveness Cross-Disciplinary Training Program (CIHR-DSECT), CIHR, and the Michael Smith Foundation for Health Research during the period of this study.

Author information


  1. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    • Allison M. Matthews PhD
    • , Magda Price PhD
    • , Jill Mwenifumbo PhD
    • , Alison M. Elliott PhD
    • , Wyeth W. Wasserman PhD
    •  & Margaret L. McKinnon MD
  2. BC Children’s Hospital Research Institute, Vancouver, BC, Canada

    • Allison M. Matthews PhD
    • , Ingrid Blydt-Hansen BSc
    • , Magda Price PhD
    • , Katherine Selby MD
    • , Michelle Demos MD
    • , Mary Connolly MD
    • , Britt Drögemoller PhD
    • , Casper Shyr PhD
    • , Jill Mwenifumbo PhD
    • , Alison M. Elliott PhD
    • , Jessica Lee PhD
    • , Aisha Ghani BSc
    • , Sylvia Stöckler MD PhD
    • , Ramona Salvarinova MD MSc
    • , Graham Sinclair PhD
    • , Colin J. Ross PhD
    • , Wyeth W. Wasserman PhD
    • , Margaret L. McKinnon MD
    • , Gabriella A. Horvath MD PhD
    •  & Clara D. van Karnebeek MD, PhD
  3. Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada

    • Allison M. Matthews PhD
    • , Magda Price PhD
    • , Hilary Vallance MD
    • , Wyeth W. Wasserman PhD
    •  & Clara D. van Karnebeek MD, PhD
  4. Department of Pediatrics, University of Alberta, Edmonton, AB, Canada

    • Basmah Al-Jabri MD
    • , John Andersen MD
    •  & Helly Goez MD
  5. Department of Pediatrics, King Abdul Aziz University, Jeddah, Saudi Arabia

    • Basmah Al-Jabri MD
  6. Department of Physical Medicine & Rehabilitation, University of Alberta, Edmonton, AB, Canada

    • John Andersen MD
  7. Departments of Biochemistry, Molecular Biology, and Medical Genetics, Cumming School of Medicine, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada

    • Maja Tarailo-Graovac PhD
  8. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

    • Katherine Selby MD
    • , Michelle Demos MD
    • , Mary Connolly MD
    • , Sylvia Stöckler MD PhD
    • , Ramona Salvarinova MD MSc
    • , Gabriella A. Horvath MD PhD
    •  & Clara D. van Karnebeek MD, PhD
  9. Department of Pathology and Laboratory medicine, University of British Columbia, Vancouver, BC, Canada

    • Hilary Vallance MD
    •  & Graham Sinclair PhD
  10. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

    • Colin J. Ross PhD
  11. Departments of Pediatrics and Clinical Genetics, Amsterdam University Medical Centres, Amsterdam, The Netherlands

    • Clara D. van Karnebeek MD, PhD


  1. Search for Allison M. Matthews PhD in:

  2. Search for Ingrid Blydt-Hansen BSc in:

  3. Search for Basmah Al-Jabri MD in:

  4. Search for John Andersen MD in:

  5. Search for Maja Tarailo-Graovac PhD in:

  6. Search for Magda Price PhD in:

  7. Search for Katherine Selby MD in:

  8. Search for Michelle Demos MD in:

  9. Search for Mary Connolly MD in:

  10. Search for Britt Drögemoller PhD in:

  11. Search for Casper Shyr PhD in:

  12. Search for Jill Mwenifumbo PhD in:

  13. Search for Alison M. Elliott PhD in:

  14. Search for Jessica Lee PhD in:

  15. Search for Aisha Ghani BSc in:

  16. Search for Sylvia Stöckler MD PhD in:

  17. Search for Ramona Salvarinova MD MSc in:

  18. Search for Hilary Vallance MD in:

  19. Search for Graham Sinclair PhD in:

  20. Search for Colin J. Ross PhD in:

  21. Search for Wyeth W. Wasserman PhD in:

  22. Search for Margaret L. McKinnon MD in:

  23. Search for Gabriella A. Horvath MD PhD in:

  24. Search for Helly Goez MD in:

  25. Search for Clara D. van Karnebeek MD, PhD in:


  1. On behalf of TIDE BC, United for Metabolic Diseases and the CAUSES Study


    The authors declare no conflicts of interest.

    Corresponding author

    Correspondence to Clara D. van Karnebeek MD, PhD.

    Electronic supplementary material

    About this article

    Publication history