title: A genomic copy number variant analysis implicates the MBD5 and HNRNPU genes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion.
abstract: BACKGROUND
  Infantile spasms (IS) is a specific type of epileptic encephalopathy associated with severe developmental disabilities. Genetic factors are strongly implicated in IS, however, the exact genetic defects remain unknown in the majority of cases. Rare mutations in a single gene or in copy number variants (CNVs) have been implicated in IS of children in Western countries. The objective of this study was to dissect the role of copy number variations in Chinese children with infantile spasms.
  
  
  METHODS
  We used the Agilent Human Genome CGH microarray 180 K for genome-wide detection of CNVs. Real-time qPCR was used to validate the CNVs. We performed genomic and medical annotations for individual CNVs to determine the pathogenicity of CNVs related to IS.
  
  
  RESULTS
  We report herein the first genome-wide CNV analysis in children with IS, detecting a total of 14 CNVs in a cohort of 47 Chinese children with IS. Four CNVs (4/47 = 8.5%) (1q21.1 gain; 1q44, 2q31.1, and 17p13 loss) are considered to be pathogenic. The CNV loss at 17p13.3 contains PAFAH1B1 (LIS1), a causative gene for lissencephaly. Although the CNVs at 1q21.1, 1q44, and 2q23.1 have been previously implicated in a wide spectrum of clinical features including autism spectrum disorders (ASD) and generalized seizure, our study is the first report identifying them in individuals with a primary diagnosis of IS. The CNV loss in the 1q44 region contains HNRNPU, a strong candidate gene recently suggested in IS by the whole exome sequencing of children with IS. The CNV loss at 2q23.1 includes MBD5, a methyl-DNA binding protein that is a causative gene of ASD and a candidate gene for epileptic encephalopathy. We also report a distinct clinical presentation of IS, microcephaly, intellectual disability, and absent hallux in a case with the 2q23.1 deletion.
  
  
  CONCLUSIONS
  Our findings strongly support the role of CNVs in infantile spasms and expand the clinical spectrum associate with 2q23.1 deletion. In particular, our study implicates the HNRNPU and MBD5 genes in Chinese children with IS. Our study also supports that the molecular mechanisms of infantile spasms appear conserved among different ethnic backgrounds.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Du
authors.forename: Yu
authors.initials: Y
authors.lastname: An
authors.forename: Lifei
authors.initials: L
authors.lastname: Yu
authors.forename: Renchao
authors.initials: R
authors.lastname: Liu
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Qin
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Guo
authors.forename: Daokan
authors.initials: D
authors.lastname: Sun
authors.forename: Shuizhen
authors.initials: S
authors.lastname: Zhou
authors.forename: Bailin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Division of Neurology, Children's Hospital of Fudan University, 399 Wan Yuan Road, Shanghai 201102, China. yong-hui.jiang@duke.edu.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics; D017668:Age of Onset; D001921:Brain / Q000473:pathology; D002675:Child, Preschool; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics*; D019066:Facies; D005260:Female; D005532:Foot Deformities, Congenital; D006228:Hand Deformities, Congenital; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D010641:Phenotype; D013036:Spasms, Infantile / Q000175:diagnosis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C550332:MBD5 protein, human; D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human