Array Comparative Genomic Hybridization as a Diagnostic Tool for Syndromic Heart Defects
Received 29 June 2009; received in revised form 10 October 2009; accepted 13 November 2009. published online 08 February 2010.
Objectives
To investigate different aspects of the introduction of array comparative genomic hybridization (aCGH) in clinical practice.
Study design
A total 150 patients with a syndromic congenital heart defect (CHD) of unknown cause were analyzed with aCGH at 1-Mb resolution. Twenty-nine of these patients, with normal results on 1Mb aCGH, underwent re-analysis with 244-K oligo-microarray. With a logistic regression model, we assessed the predictive value of patient characteristics for causal imbalance detection. On the basis of our earlier experience and the literature, we constructed an algorithm to evaluate the causality of copy number variants.
Results
With 1-Mb aCGH, we detected 43 structural variants not listed as clinically neutral polymorphisms, 26 of which were considered to be causal. A systematic comparison of the clinical features of these 26 patients to the remaining 124 patients revealed dysmorphism as the only feature with a significant predictive value for reaching a diagnosis with 1-Mb aCGH. With higher resolution analysis in 29 patients, 75 variants not listed as clinically neutral polymorphisms were detected, 2 of which were considered to be causal.
Conclusions
Molecular karyotyping yields an etiological diagnosis in at least 18% of patients with a syndromic CHD. Higher resolution evaluation results in an increasing number of variants of unknown significance.
aCenter of Human Genetics, University Hospitals Leuven, Leuven, Belgium
bDepartment of Pediatric and Congenital Cardiology, University Hospital Gasthuisberg, Leuven, Belguim
cPediatric Cardiology Unit, University Hospitals Leuven, Leuven, Belgium
dClinical Genetics, Kaplan Medical Center, Rehovot, Israel
eNeonatology Unit, University Hospitals Leuven, Leuven, Belgium
Reprint requests: Prof Dr Koenraad Devriendt, Center of Human Genetics, University Hospitals Leuven, Herestraat 49 bus 602, B-3000 Leuven, Belgium.
Supported by grants from the FWO (FWOG.0254.05) and the Belgian program of Interuniversity Poles of attraction (GOA/2006/12). K.D. is a senior clinical investigator and J.B. is an aspirant investigator of the FWO Vlaanderen. B.T. is supported by a grant from the IWT Vlaanderen. The other authors declare no conflicts of interest.
ABSTRACT