Genes and Genomics

The Genetics Society of Korea (한국유전학회)
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Identification of pathways and genes associated with cerebral palsy

  • Zhu, Qingwen (Prenatal Screening and Diagnosis Center, Nantong Municipal Maternal and Child Health Hospital) ;
  • Ni, Yufei (Prenatal Screening and Diagnosis Center, Nantong Municipal Maternal and Child Health Hospital) ;
  • Wang, Jing (Prenatal Screening and Diagnosis Center, Nantong Municipal Maternal and Child Health Hospital) ;
  • Yin, Honggang (Prenatal Screening and Diagnosis Center, Nantong Municipal Maternal and Child Health Hospital) ;
  • Zhang, Qin (Prenatal Screening and Diagnosis Center, Nantong Municipal Maternal and Child Health Hospital) ;
  • Zhang, Lingli (Prenatal Screening and Diagnosis Center, Nantong Municipal Maternal and Child Health Hospital) ;
  • Bian, Wenjun (Prenatal Screening and Diagnosis Center, Nantong Municipal Maternal and Child Health Hospital) ;
  • Liang, Bo (Basecare Medical Device Co., Ltd.) ;
  • Kong, Lingyin (Basecare Medical Device Co., Ltd.) ;
  • Xuan, Liming (Basecare Medical Device Co., Ltd.) ;
  • Lu, Naru (Basecare Medical Device Co., Ltd.)
  • Received : 2018.04.24
  • Accepted : 2018.08.12
  • Published : 2018.12.31
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Abstract

Cerebral palsy (CP) is a non-progressive neurological disease, of which susceptibility is linked to genetic and environmental risk factors. More and more studies have shown that CP might be caused by multiple genetic factors, similar to other neurodevelopmental disorders. Due to the high genetic heterogeneity of CP, we focused on investigating related molecular pathways. Ten children with CP were collected for whole-exome sequencing by next-generation sequencing (NGS) technology. Customized processes were used to identify potential pathogenic pathways and variants. Three pathways (axon guidance, transmission across chemical synapses, protein-protein interactions at synapses) with twenty-three genes were identified to be highly correlated with CP. This study showed that the three pathways associated with CP might be the molecular mechanism of pathogenesis. These findings could provide useful clues for developing pathway-based pharmacotherapies. Further studies are required to confirm potential roles for these pathways in the pathogenesis of CP.

Keywords

Acknowledgement

Supported by : Jiangsu Province Association of Maternal and Child Health (JSPAMACH)

References

  1. Betancur C (2011) Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 1380:42-77. https://doi.org/10.1016/j.brainres.2010.11.078
  2. Betancur C, Sakurai T, Buxbaum JD (2009) The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci 32(7):402-412. https://doi.org/10.1016/j.tins.2009.04.003
  3. Eilbeck K, Quinlan A, Yandell M (2017) Settling the score: variant prioritization and Mendelian disease. Nat Rev Genet 18(10):599-612. https://doi.org/10.1038/nrg.2017.52
  4. Fahey MC, Maclennan AH, Kretzschmar D, Gecz J, Kruer MC (2017) The genetic basis of cerebral palsy. Dev Med Child Neurol 59(5):462-469. https://doi.org/10.1111/dmcn.13363
  5. Farlow JL, Robak LA, Hetrick K, Bowling K, Boerwinkle E, Coban-Akdemir ZH et al (2016) Whole-exome sequencing in familial Parkinson disease. JAMA Neurol 73(1):68-75. https://doi.org/10.1001/jamaneurol.2015.3266
  6. Fujita PA, Rhead B, Zweig AS, Hinrichs AS, Karolchik D, Cline MS et al (2011) The UCSC Genome Browser database: update 2011. Nucleic Acids Res 39(Database issue):D876-D882. https://doi.org/10.1093/nar/gkq963
  7. Genomes Project C, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM et al (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491(7422):56-65. https://doi.org/10.1038/nature11632
  8. Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA (2005) Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 33(Database issue):D514-D517. https://doi.org/10.1093/nar/gki03 3
  9. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S et al (2016) REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 99(4):877-885. https://doi.org/10.1016/j.ajhg.2016.08.016
  10. Jagadeesh KA, Wenger AM, Berger MJ, Guturu H, Stenson PD, Cooper DN et al (2016) M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet 48(12):1581-1586. https://doi.org/10.1038/ng.3703
  11. Jeong H, Huh HJ, Youn J, Kim JS, Cho JW, Ki CS (2014) Ataxia-telangiectasia with novel splicing mutations in the ATM gene. Ann Lab Med 34(1):80-84. https://doi.org/10.3343/alm.2014.34.1.80
  12. Jian X, Boerwinkle E, Liu X (2014) In silico prediction of splicealtering single nucleotide variants in the human genome. Nucleic Acids Res 42(22):13534-13544. https://doi.org/10.1093/nar/gku1206
  13. Joshi-Tope G, Gillespie M, Vastrik I, D'Eustachio P, Schmidt E, de Bono B et al (2005) Reactome: a knowledgebase of biological pathways. Nucleic Acids Res 33(Database issue):D428-D432. https://doi.org/10.1093/nar/gki07 2
  14. Kasapkara CS, Akar M, Ozbek MN, Tuzun H, Aldudak B, Baran RT, Tanyalcin T (2015) Mutations in BTD gene causing biotinidase deficiency: a regional report. J Pediatr Endocrinol Metab 28(3-4):421-424. https://doi.org/10.1515/jpem-2014-0056
  15. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46(3):310-315. https://doi.org/10.1038/ng.2892
  16. Kruer MC, Jepperson T, Dutta S, Steiner RD, Cottenie E, Sanford L et al (2013) Mutations in gamma adducin are associated with inherited cerebral palsy. Ann Neurol 74(6):805-814. https://doi.org/10.1002/ana.23971
  17. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42(Database issue):D980-D985. https://doi.org/10.1093/nar/gkt1113
  18. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285-291. https://doi.org/10.1038/nature19057
  19. Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26(5):589-595. https://doi.org/10.1093/bioinformatics/btp698
  20. Lin S, Li T, Zhu D, Ma C, Wang Y, He L et al (2013) The association between GAD1 gene polymorphisms and cerebral palsy in Chinese infants. Cytol Genet 47(5):276-281. https://doi.org/10.3103/s0095452713050071
  21. Liu X, Jian X, Boerwinkle E (2011) dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat 32(8):894-899. https://doi.org/10.1002/humu.21517
  22. MacLennan AH, Thompson SC, Gecz J (2015) Cerebral palsy: causes, pathways, and the role of genetic variants. Am J Obstet Gynecol 213(6):779-788. https://doi.org/10.1016/j.ajog.2015.05.034
  23. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297-1303. https://doi.org/10.1101/gr.107524.110
  24. McMichael G, Girirajan S, Moreno-De-Luca A, Gecz J, Shard C, Nguyen LS et al (2014) Rare copy number variation in cerebral palsy. Eur J Hum Genet 22(1):40-45. https://doi.org/10.1038/ejhg.2013.93
  25. McMichael G, Bainbridge MN, Haan E, Corbett M, Gardner A, Thompson S et al (2015) Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy. Mol Psychiatry 20(2):176-182. https://doi.org/10.1038/mp.2014.189
  26. Moreno-De-Luca A, Ledbetter DH, Martin CL (2012) Genetic insights into the causes and classification of the cerebral palsies. Lancet Neurol 11(3):283-292. https://doi.org/10.1016/s1474-4422(11)70287 -3
  27. Nolt MJ, Lin Y, Hruska M, Murphy J, Sheffler-Colins SI, Kayser MS et al (2011) EphB controls NMDA receptor function and synaptic targeting in a subunit-specific manner. J Neurosci 31(14):5353-5364. https://doi.org/10.1523/JNEUROSCI.0282-11.2011
  28. Nunez JL, McCarthy MM (2004) Cell death in the rat hippocampus in a model of prenatal brain injury: time course and expression of death-related proteins. Neuroscience 129(2):393-402. https://doi.org/10.1016/j.neuro science.2004.08.006
  29. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB (2013) Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet 9(8):e1003709. https://doi.org/10.1371/journal.pgen.10037 09
  30. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) 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 17(5):405-424. https://doi.org/10.1038/gim.2015.30
  31. Roy S, Coldren C, Karunamurthy A, Kip NS, Klee EW, Lincoln SE et al (2018) Standards and guidelines for validating next-generation sequencing bioinformatics pipelines: a joint recommendation of the Association for Molecular Pathology and the College of American Pathologists. J Mol Diagn 20(1):4-27. https://doi.org/10.1016/j.jmold x.2017.11.003
  32. Segel R, Ben-Pazi H, Zeligson S, Fatal-Valevski A, Aran A, Gross-Tsur V et al (2015) Copy number variations in cryptogenic cerebral palsy. Neurology 84(16):1660-1668. https://doi.org/10.1212/wnl.0000000000001494
  33. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29(1):308-311. https://doi.org/10.1093/nar/29.1.308
  34. Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M et al (2010) Towards a knowledge-based human protein atlas. Nat Biotechnol 28(12):1248-1250. https://doi.org/10.1038/nbt1210-1248
  35. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347(6220):1260419. https://doi.org/10.1126/science.1260419
  36. Vernau K, Napoli E, Wong S, Ross-Inta C, Cameron J, Bannasch D et al (2015) Thiamine deficiency-mediated brain mitochondrial pathology in Alaskan Huskies with mutation in SLC19A3.1. Brain Pathol 25(4):441-453. https://doi.org/10.1111/bpa.12188
  37. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164. https://doi.org/10.1093/nar/gkq603
  38. Wang H, Xu Y, Chen M, Shang Q, Sun Y, Zhu D et al (2013) Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population. Mol Biol Rep 40(11):6459-6467. https://doi.org/10.1007/s1103 3-013-2761-6
  39. Yang H, Robinson PN, Wang K (2015) Phenolyzer: phenotype-based prioritization of candidate genes for human diseases. Nat Methods 12(9):841-843. https://doi.org/10.1038/nmeth.3484

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