title: High resolution chromosomal microarray in undiagnosed neurological disorders.
abstract: OBJECTIVE
  Despite advances in medical investigation, many children with neurological conditions remain without a diagnosis, although a genetic aetiology is often suspected. Chromosomal microarray (CMA) screens for copy number variants (CNVs) and long continuous stretches of homozygosity (LCSH) and may further enhance diagnostic yield. Although recent studies have identified pathogenic CNVs in intellectual disability, autism and epilepsy, the utility of CMA testing in a broader cohort of children with neurologic disorders has not been reported.
  
  
  METHODS
  Two hundred fifteen patients with neurological conditions of unknown aetiology were seen over a 6-month period and were prospectively tested by CMA using high-resolution single nucleotide polymorphism (SNP) microarrays (Illumina HumanCytoSNP-12 v2.1 or Affymetrix 2.7M).
  
  
  RESULTS
  Thirty of 215 (14%) patients tested had an abnormal CMA. Twenty-nine had CNVs (13%) and one (0.5%) a clinically significant stretch of homozygosity. Twenty (9.3%) had a CMA finding considered to be pathogenic or involved in susceptibility to the condition of interest, and 10 (4.7%) had findings of unknown significance. Their phenotypes included infantile spasms and other epilepsies, neuromuscular conditions, ataxia, movement disorders, microcephaly and malformations of cortical development. At least one third of patients did not meet national funding criteria for CMA at the time of presentation.
  
  
  CONCLUSIONS
  CMA detected clinically significant abnormalities in a broad range of neurologic phenotypes of unknown aetiology. This test should be considered a first-tier investigation of children with neurologic disorders in whom the initial clinical assessment does not indicate a likely aetiology, especially those with severe epilepsies and neurologically abnormal neonates.
authors.affiliation: Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Howell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kornberg
authors.forename: A Simon
authors.initials: AS
authors.lastname: Harvey
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.forename: Mark T
authors.initials: MT
authors.lastname: Mackay
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Freeman
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Rodriguez Casero
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Collins
authors.forename: Michael
authors.initials: M
authors.lastname: Hayman
authors.forename: Ahmad
authors.initials: A
authors.lastname: Mohamed
authors.forename: Tyson L
authors.initials: TL
authors.lastname: Ware
authors.forename: Damian
authors.initials: D
authors.lastname: Clark
authors.forename: Damien L
authors.initials: DL
authors.lastname: Bruno
authors.forename: Trent
authors.initials: T
authors.lastname: Burgess
authors.forename: Howard
authors.initials: H
authors.lastname: Slater
authors.forename: George
authors.initials: G
authors.lastname: McGillivray
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
mesh_terms: D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009422:Nervous System Diseases / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
keywords: chromosomal microarray; copy number variant; long continuous stretch homozygosity; single nucleotide polymorphism microarray.