Subjects

Abstract

Purpose

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).

Methods

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.

Results

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%).

Conclusion

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.

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Additional information

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

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Acknowledgements

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

Affiliations

  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

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Consortia

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

    Disclosure

    The authors declare no conflicts of interest.

    Corresponding author

    Correspondence to Clara D. van Karnebeek MD, PhD.

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    DOI

    https://doi.org/10.1038/s41436-018-0376-y