title: Array comparative genomic hybridization and fetal congenital heart defects: a systematic review and meta-analysis.
abstract: OBJECTIVE
  Array comparative genomic hybridization (aCGH) is a molecular cytogenetic technique that is able to detect the presence of copy number variants (CNVs) within the genome. The detection rate of imbalances by aCGH compared to standard karyotyping and 22q11 microdeletion analysis by fluorescence in-situ hybridization (FISH), in the setting of prenatally-diagnosed cardiac malformations, has been reported in several studies. The objective of our study was to perform a systematic literature review and meta-analysis to document the additional diagnostic gain of using aCGH in cases of congenital heart disease (CHD) diagnosed by prenatal ultrasound examination, with the aim of assisting clinicians to determine whether aCGH analysis is warranted when an ultrasonographic diagnosis of CHD is made, and to guide counseling in this setting.
  
  
  METHODS
  Articles in PubMed, EMBASE and Web of Science databases from January 2007 to September 2014 describing CNVs in prenatal cases of CHD were included. Search terms were: 'array comparative genomic hybridization', 'copy number variants' and 'fetal congenital heart defects'. Articles regarding karyotyping or 22q11 deletion only were excluded.
  
  
  RESULTS
  Thirteen publications (including 1131 cases of CHD) met the inclusion criteria for the analysis. Meta-analysis indicated an incremental yield of 7.0% (95% CI, 5.3-8.6%) for the detection of CNVs using aCGH, excluding aneuploidy and 22q11 microdeletion cases. Subgroup results showed a 3.4% (95% CI, 0.3-6.6%) incremental yield in isolated CHD cases, and 9.3% (95% CI,  6.6-12%) when extracardiac malformations were present. Overall, an incremental yield of 12% (95% CI, 7.6-16%) was found when 22q11 deletion cases were included. There was an additional yield of 3.4% (95% CI, 2.1-4.6%) for detecting variants of unknown significance (VOUS).
  
  
  CONCLUSIONS
  In this review we provide an overview of published data and discuss the benefits and limitations of using aCGH. If karyotyping and 22q11 microdeletion analysis by FISH are normal, using aCGH has additional value, detecting pathogenic CNVs in 7.0% of prenatally diagnosed CHD, with a 3.4% additional yield of detecting VOUS.
authors.affiliation: Leiden University Medical Center, Department of Obstetrics and Fetal Medicine, Leiden, The Netherlands.
authors.forename: F A R
authors.initials: FA
authors.lastname: Jansen
authors.forename: Y J
authors.initials: YJ
authors.lastname: Blumenfeld
authors.forename: A
authors.initials: A
authors.lastname: Fisher
authors.forename: J M
authors.initials: JM
authors.lastname: Cobben
authors.forename: A O
authors.initials: AO
authors.lastname: Odibo
authors.forename: A
authors.initials: A
authors.lastname: Borrell
authors.forename: M C
authors.initials: MC
authors.lastname: Haak
mesh_terms: D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D005817:Genetic Counseling; D006330:Heart Defects, Congenital / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D007621:Karyotyping; D046228:Microarray Analysis; D011247:Pregnancy; D011296:Prenatal Diagnosis
keywords: array comparative genomic hybridization; congenital heart defects; copy number variants; prenatal diagnosis