Clinically relevant copy number variations detected in cerebral palsy

Maryam Oskoui, Matthew J Gazzellone, Bhooma Thiruvahindrapuram, Mehdi Zarrei, John Andersen, John Wei, Zhuozhi Wang, Richard F Wintle, Christian R Marshall, Ronald D Cohn, Rosanna Weksberg, Dimitri J Stavropoulos, Darcy Fehlings, Michael I Shevell, Stephen W Scherer, Maryam Oskoui, Matthew J Gazzellone, Bhooma Thiruvahindrapuram, Mehdi Zarrei, John Andersen, John Wei, Zhuozhi Wang, Richard F Wintle, Christian R Marshall, Ronald D Cohn, Rosanna Weksberg, Dimitri J Stavropoulos, Darcy Fehlings, Michael I Shevell, Stephen W Scherer

Abstract

Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age of onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of aetiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (∼1% rate in controls). In four children, large chromosomal abnormalities deemed likely pathogenic were found, and they were significantly more likely to have severe neuromotor impairments than those CP subjects without such alterations. Overall, the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families.

Figures

Figure 1. CNVs affecting PARK2 and PACRG…
Figure 1. CNVs affecting PARK2 and PACRG.
The de novo duplication in patient 13-009C impacting both PARK2 and PACRG is illustrated by the blue bar above. Inherited deletions (denoted by the red bars) have been identified in exon 4 of PARK2 (NM_004562.2) in subject 8-03C and in exon 4 of PACRG (NM_152410.2) in subject 3-07C.

References

    1. Oskoui M., Coutinho F., Dykeman J., Jette N. & Pringsheim T. An update on the prevalence of cerebral palsy: a systematic review and meta-analysis. Dev. Med. Child Neurol. 55, 509–519 (2013).
    1. Himmelmann K., Ahlin K., Jacobsson B., Cans C. & Thorsen P. Risk factors for cerebral palsy in children born at term. Acta Obstet. Gynecol. Scand. 90, 1070–1081 (2011).
    1. McIntyre S. et al.. A systematic review of risk factors for cerebral palsy in children born at term in developed countries. Dev. Med. Child Neurol. 55, 499–508 (2013).
    1. Beaino G. et al.. Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. Dev. Med. Child Neurol. 52, e119–e125 (2010).
    1. Ellenberg J. H. & Nelson K. B. The association of cerebral palsy with birth asphyxia: a definitional quagmire. Dev. Med. Child Neurol. 55, 210–216 (2013).
    1. Rosenbaum P. et al.. A report: the definition and classification of cerebral palsy April 2006. Dev. Med. Child Neurol. Suppl. 109, 8–14 (2007).
    1. Wood E. & Rosenbaum P. The gross motor function classification system for cerebral palsy: a study of reliability and stability over time. Dev. Med. Child Neurol. 42, 292–296 (2000).
    1. Hemminki K., Li X., Sundquist K. & Sundquist J. High familial risks for cerebral palsy implicate partial heritable aetiology. Paediatr. Perinat. Epidemiol. 21, 235–241 (2007).
    1. Amor D. J., Craig J. E., Delatycki M. B. & Reddihough D. Genetic factors in athetoid cerebral palsy. J. Child Neurol. 16, 793–797 (2001).
    1. Lynex C. N. et al.. Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders. BMC Neurol. 4, 20 (2004).
    1. Lundy C., Lumsden D. & Fairhurst C. Treating complex movement disorders in children with cerebral palsy. Ulster Med. J. 78, 157–163 (2009).
    1. Lerer I. et al.. Deletion of the ANKRD15 gene at 9p24.3 causes parent-of-origin-dependent inheritance of familial cerebral palsy. Hum. Mol. Genet. 14, 3911–3920 (2005).
    1. Kakinuma N., Zhu Y., Wang Y., Roy B. C. & Kiyama R. Kank proteins: structure, functions and diseases. Cell. Mol. Life Sci. 66, 2651–2659 (2009).
    1. Moreno-De-Luca A. et al.. Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J. Med. Genet. 48, 141–144 (2011).
    1. Moreno-De-Luca A., Ledbetter D. H. & Martin C. L. Genetic [corrected] insights into the causes and classification of [corrected] cerebral palsies. Lancet Neurol. 11, 283–292 (2012).
    1. Matsuda S. & Yuzaki M. Polarized sorting of AMPA receptors to the somatodendritic domain is regulated by adaptor protein AP-4. Neurosci. Res. 65, 1–5 (2009).
    1. Ashwal S. et al.. Practice parameter: diagnostic assessment of the child with cerebral palsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 62, 851–863 (2004).
    1. Shevell M., Miller S. P., Scherer S. W., Yager J. Y. & Fehlings M. G. The Cerebral Palsy Demonstration Project: a multidimensional research approach to cerebral palsy. Semin. Pediatr. Neurol. 18, 31–39 (2011).
    1. Gazzellone M. J. et al.. Copy number variation in Han Chinese individuals with autism spectrum disorder. J. Neurodev. Disord. 6, 34 (2014).
    1. MacDonald J. R., Ziman R., Yuen R. K., Feuk L. & Scherer S. W. The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 42, D986–D992 (2014).
    1. de Leeuw N. et al.. Diagnostic interpretation of array data using public databases and internet sources. Hum. Mutat. 33, 930–940 (2012).
    1. Miller D. T. 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. 86, 749–764 (2010).
    1. Brunetti-Pierri N. et al.. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat. Genet. 40, 1466–1471 (2008).
    1. Lee C. & Scherer S. W. The clinical context of copy number variation in the human genome. Expert Rev. Mol. Med. 12, e8 (2010).
    1. Ramalingam A. et al.. 16p13.11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders. J. Hum. Genet. 56, 541–544 (2011).
    1. West A. B., Lockhart P. J., O'Farell C. & Farrer M. J. Identification of a novel gene linked to parkin via a bi-directional promoter. J. Mol. Biol. 326, 11–19 (2003).
    1. Pankratz N. et al.. Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations. Neurology 73, 279–286 (2009).
    1. Bueter W., Dammann O. & Leviton A. Endoplasmic reticulum stress, inflammation, and perinatal brain damage. Pediatr. Res. 66, 487–494 (2009).
    1. Kadotani T. et al.. A chomosomal study on 100 cases of cerebral palsy. Int. J. Hum. Genet. 1, 109–112 (2001).
    1. Segel R. et al.. Copy number variations in cryptogenic cerebral palsy. Neurology 84, 1660–1668 (2015).
    1. McMichael G. et al.. Rare copy number variation in cerebral palsy. Eur. J. Hum. Genet. 22, 40–45 (2014).
    1. Parolin Schnekenberg R. et al.. De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain 138, 1817–1832 (2015).
    1. McMichael G. et al.. Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy. Mol. Psychiatry 20, 176–182 (2015).
    1. Scherer S. W. et al.. Challenges and standards in integrating surveys of structural variation. Nat. Genet. 39, S7–15 (2007).
    1. Pinto D., Marshall C., Feuk L. & Scherer S. W. Copy-number variation in control population cohorts. Hum. Mol. Genet. 16, R168–R173 (2007).
    1. Pinto D. et al.. Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat. Biotechnol. 29, 512–520 (2011).
    1. Wang K. et al.. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 17, 1665–1674 (2007).
    1. Colella S. et al.. QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res. 35, 2013–2025 (2007).
    1. Purcell S. et al.. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
    1. Pinto D. et al.. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010).
    1. Zarrei M., MacDonald J. R., Merico D. & Scherer S. W. A copy number variation map of the human genome. Nat. Rev. Genet. 16, 172–183 (2015).
    1. Verhoeven V. J. et al.. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nat. Genet. 45, 314–318 (2013).
    1. Bierut L. J. et al.. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum. Mol. Genet. 16, 24–35 (2007).
    1. Stewart A. F. et al.. Kinesin family member 6 variant Trp719Arg does not associate with angiographically defined coronary artery disease in the Ottawa Heart Genomics Study. J. Am. Coll. Cardiol. 53, 1471–1472 (2009).
    1. Krawczak M. et al.. PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Community. Genet. 9, 55–61 (2006).
    1. Bierut L. J. et al.. A genome-wide association study of alcohol dependence. Proc. Natl Acad. Sci. USA 107, 5082–5087 (2010).
    1. Cotterchio M. et al.. Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes, and colorectal cancer risk. Cancer Epidemiol. Biomarkers Prev. 17, 3098–3107 (2008).
    1. Coviello A. D. et al.. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. PLoS Genet. 8, e1002805 (2012).
    1. Uddin M. et al.. A high-resolution copy-number variation resource for clinical and population genetics. Genet. Med. doi:10.1038/gim.2014.178 (2014).
    1. Lionel A. C. et al.. Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci. Transl. Med. 3, 95ra75 (2011).
    1. Elia J. et al.. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat. Genet. 44, 78–84 (2012).
    1. Sebat J. et al.. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).
    1. Pinto D. et al.. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am. J. Hum. Genet. 94, 677–694 (2014).
    1. Noor A. et al.. Copy number variant study of bipolar disorder in Canadian and UK populations implicates synaptic genes. Am. J. Med. Genet. B Neuropsychiatr. Genet. 165B, 303–313 (2014).
    1. Malhotra D. et al.. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011).
    1. Olson H. et al.. Copy number variation plays an important role in clinical epilepsy. Ann. Neurol. 75, 943–958 (2014).
    1. Gilissen C. et al.. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).
    1. Qiao Y. et al.. Copy number variants (CNVs) analysis in a deeply phenotyped cohort of individuals with intellectual disability (ID). BMC Med. Genet. 15, 82 (2014).
    1. Kirov G. et al.. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142–153 (2012).
    1. Sanders S. J. et al.. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011).

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