title: Identification of clinically significant, submicroscopic chromosome alterations and UPD in fetuses with ultrasound anomalies using genome-wide 250k SNP array analysis.
abstract: BACKGROUND
  The implementation of microarray analysis in prenatal diagnostics is a topic of discussion, as rare copy number variants with unknown/uncertain clinical consequences are likely to be found. The application of targeted microarrays limits such findings, but the potential disadvantage is that relevant, so far unknown, aberrations might be overlooked. Therefore, we explore the possibilities for the prenatal application of the genome-wide 250k single nucleotide polymorphism array platform.
  
  
  METHODS
  Affymetrix 250k NspI single nucleotide polymorphism array analysis (Affymetrix, Inc., Santa Clara, California, USA) was performed on DNA from 38 prenatally karyotyped fetuses with ultrasound anomalies. Analyses were performed after termination of pregnancy, intrauterine fetal death or birth on DNA isolated from fetal or neonatal material.
  
  
  RESULTS
  Aberrations were detected in 17 of 38 fetuses, 6 of whom with a previously identified chromosomal abnormality and 11 with previously normal or balanced karyotypes. Of the latter, the detected aberration occurred de novo and was considered of clinical relevance in five cases (16%), inherited from a healthy parent in four cases (12%), and de novo yet with unclear clinical relevance in two cases (6%). The clinically relevant abnormalities either were novel copy number variants (n=3) or concerned a uniparental disomy (n=2).
  
  
  CONCLUSIONS
  In at least 16% of fetuses with ultrasound anomalies and a normal or balanced karyotype, causal (submicroscopic) aberrations were detected, illustrating the importance of the (careful) implementation of microarray analysis in prenatal diagnosis. The fact that the identified, clinically relevant, aberrations would have gone undetected with most targeted approaches underscores the added value of a genome-wide approach.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. b.faas@antrg.umcn.nl
authors.forename: B H W
authors.initials: BH
authors.lastname: Faas
authors.forename: I
authors.initials: I
authors.lastname: van der Burgt
authors.forename: A J A
authors.initials: AJ
authors.lastname: Kooper
authors.forename: R
authors.initials: R
authors.lastname: Pfundt
authors.forename: J Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.forename: A P T
authors.initials: AP
authors.lastname: Smits
authors.forename: N
authors.initials: N
authors.lastname: de Leeuw
mesh_terms: D020029:Base Pairing / Q000235:genetics; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D005333:Fetus / Q000473:pathology*; D015894:Genome, Human / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy; D016216:Ultrasonography, Prenatal; D024182:Uniparental Disomy / Q000175:diagnosis / Q000235:genetics*