title: Clinical relevance of small copy-number variants in chromosomal microarray clinical testing.
abstract: The 2010 consensus statement on diagnostic chromosomal microarray (CMA) testing recommended an array resolution ≥400 kb throughout the genome as a balance of analytical and clinical sensitivity. In spite of the clear evidence for pathogenicity of large copy-number variants (CNVs) in neurodevelopmental disorders and/or congenital anomalies, the significance of small, nonrecurrent CNVs (<500 kb) has not been well established in a clinical setting.
  
  
  
  We investigated the clinical significance of all nonpolymorphic small, nonrecurrent CNVs (<500 kb) in patients referred for CMA clinical testing over a period of 6 years, from 2009 to 2014 (a total of 4,417 patients). We excluded from our study patients with benign or likely benign CNVs and patients with only recurrent microdeletions/microduplications <500 kb.
  
  
  
  In total, 383 patients (8.67%) were found to carry at least one small, nonrecurrent CNV, of whom 176 patients (3.98%) had one small CNV classified as a variant of uncertain significance (VUS), 45 (1.02%) had two or more small VUS CNVs, 20 (0.45%) had one small VUS CNV and a recurrent CNV, 113 (2.56%) had one small pathogenic or likely pathogenic CNV, 17 (0.38%) had two or more small pathogenic or likely pathogenic CNVs, and 12 (0.27%) had one small pathogenic or likely pathogenic CNV and a recurrent CNV. Within the pathogenic group, 80 of 142 patients (56% of all small pathogenic CNV cases) were found to have a single whole-gene or exonic deletion. The themes that emerged from our study are presented in the Discussion section.
  
  
  
  Our study demonstrates the diagnostic clinical relevance of small, nonrecurrent CNVs <500 kb during CMA clinical testing and underscores the need for careful clinical interpretation of these CNVs.Genet Med 19 4, 377-385.
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Hollenbeck
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Current address: Children's Health Hospital, Dallas, Texas, USA.
authors.forename: Crescenda L
authors.identifier: 0000-0003-0300-4720
authors.initials: CL
authors.lastname: Williams
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Kathryn
authors.identifier: 0000-0001-7569-9328
authors.initials: K
authors.lastname: Drazba
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Maria
authors.identifier: 0000-0002-7225-040X
authors.initials: M
authors.lastname: Descartes
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Bruce R
authors.identifier: 0000-0001-8272-339X
authors.initials: BR
authors.lastname: Korf
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: S Lane
authors.initials: SL
authors.lastname: Rutledge
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Edward J
authors.identifier: 0000-0002-9212-4101
authors.initials: EJ
authors.lastname: Lose
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Nathaniel H
authors.identifier: 0000-0001-9995-547X
authors.initials: NH
authors.lastname: Robin
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Fady M
authors.identifier: 0000-0003-3517-1902
authors.initials: FM
authors.lastname: Mikhail
mesh_terms: D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization / Q000379:methods*; D000013:Congenital Abnormalities / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D017384:Sequence Deletion