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Atypical cerebral palsy: genomics analysis enables precision medicine

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.

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Disclosure

The authors declare no conflicts of interest.

Correspondence to Clara D. van Karnebeek MD, PhD.

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Keywords

  • cerebral palsy (CP)
  • next-generation sequencing (NGS)
  • intellectual disability (ID)
  • molecular diagnosis
  • treatment