Title: Improving our Insight in the Genetic Origin of Congenital Heart defects using Array Comparative Genome Hybridization.
Other Titles: Genetica van de hartontwikkeling bij de mens. De identificatie van genen betrokken in het ontstaan van aangeboren hartafwijkingen
Authors: Thienpont, Bernard
Issue Date: 7-May-2009
Abstract: Chromosome investigations are still an important part of the genetic inv estigations in children with congenital heart defects (CHDs). For this, chromosomes from dividing white blood cells are investigated under a mic roscope to check if certain chromosomes or parts of chromosomes are pres ent in too many or too little copies. In the present work we have invest igated whether submicroscopic chromosome imbalances are a frequent cause for CHDs. We introduced a novel genome-wide copy number profiling techn ique (aCGH) and showed that it enables a reliable detection of suc h imbalances at a resolution far surpassing the resolution of microscopi c chromosome investigations. The application of this technique in patien ts with a syndromic CHD greatly enhances the chance of finding an etiolo gical diagnosis. More precisely, in 20% of them, a disease-causing submi croscopic chromosome imbalance can be demonstrated. The correct delineat ion of chromosome aberrations by aCGH also entails a more accurate chara cterization of the genotype of the patient, permitting a more personaliz ed, specific genetic diagnosis. A diagnosis is of the utmost importance for the follow-up of the patients and their families, as it allows more correct counseling of patient and parents regarding recurrence risks and the mental and physical development that can be expected. In some cases it also impacts treatment of the patients as complications associated w ith certain genetic conditions can be prevented or managed from a subcli nical stage (e.g. hearing loss or cardiac complications). We showed that the application of higher-resolution platforms enables the genome-wide identification of indel mutations of single genes (e.g. in FOXC1 or ATRX ), but that this increased resolution is accompanied by an unexpected co mplexity in the evaluation of their causality. The identification of submicroscopic indels in the DNA of syndromic CHD patients pinpoints regions that contain a gene responsible for heart dev elopment. We detected many imbalances that affect genes known to cause C HDs. Accordingly, imbalances identified in this way that do not affect k nown genes for CHDs pinpoint novel candidate regions. The use of advance d database mining strategies like ENDEAVOUR aids in ranking and selectin g valuable candidate genes from these loci, and we showed that there is room for improvement by tailoring these tools to the needs of the underl ying clinical or scientific question. We have used expression analyses i n zebrafish embryos to identify the most valuable candidates from a grou p of high-ranked candidate genes. Genes that showed a specific expressio n in the developing zebrafish heart were considered good candidate genes . Only 2 out of 24 candidate genes displayed such a pattern: BMP4 and HAND2. Both genes are excellent candidates as they were already know n to be involved in mammalian heart development through studies in mice. In one person with a CHD we detected a deletion on the long arm of chrom osome 6. In this region, our algorithm identified TAB2 as the best candi date gene for causing heart defects. This gene is deleted in multiple pa tients with CHDs, is located in the critical deletion region and is rank ed first as a candidate gene amongst over 100 genes from the region. Los s of a copy of this gene is described to be associated with a high morta lity in newborn mice, and we have shown that it is associated with devel opmental defects in zebrafish. Although we could not identify pathogenic mutations in a group of 100 patients with isolated heart defects, other s did find a disruption of this gene in 3 members of a small family that have heart defects. This shows that loss of a copy of TAB2 is a rare ca use of CHDs.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Genetics of Human Development
Clinical Genetics Section (-)
Laboratory of Translational Genetics (Vesalius Research Center) (+)

Files in This Item:
File Description Status SizeFormat
Doctoraat_BT_final_final_with_references.pdf Published 4773KbAdobe PDFView/Open


All items in Lirias are protected by copyright, with all rights reserved.