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
Subscribe to Journal
Get full journal access for 1 year
only $94.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Senior co-authors:Helly Goez and Clara D. van Karnebeek.
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.
Aisen ML, Kerkovich D, Mast J, et al. Cerebral palsy: clinical care and neurological rehabilitation. Lancet Neurol. 2011;10:844–852.
Mac Keith RC, Keith RCM, Polani PE, Lipmann K, Wheeler DE, Shepherd IDD. Cerebral palsy. Lancet. 1958;271:961–962.
Bax MCO. Terminology and classification of cerebral palsy. Dev Med Child Neurol. 1964;6:295–297.
World Health Organization. International Classification of Functioning, Disability and Health: ICF. World Health Organization; 2001.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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. https://doi.org/10.1098/rstb.2013.0514. Accessed 7 Dec. 2018.
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.
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.
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.
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.
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.
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.
Flanagan JG, Vanderhaeghen P. The ephrins and Eph receptors in neural development. Annu Rev Neurosci. 1998;21:309–345.
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.
Leighton PA, Mitchell KJ, Goodrich LV, et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature. 2001;410:174–179.
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.
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.
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.
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.
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.
MacLennan AH, Kruer MC, Baynam G, et al. Cerebral palsy and genomics: an international consortium. Dev Med Child Neurol. 2018;60:209–210.
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.
Srivastava S, Siddharth S, Cohen JS, et al. Clinical whole exome sequencing in child neurology practice. Ann Neurol. 2014;76:473–483.
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.
Karaca E, Posey JE, Coban Akdemir Z, et al. Phenotypic expansion illuminates multilocus pathogenic variation. Genet Med. 2018 Apr 26; https://doi.org/10.1038/gim.2018.33 [Epub ahead of print].
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.
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.