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Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot


Rauch, R; Hofbeck, M; Zweier, C; Koch, A; Zink, S; Trautmann, U; Hoyer, J; Kaulitz, R; Singer, H; Rauch, A (2010). Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot. Journal of Medical Genetics, 47(5):321-331.

Abstract

Tetralogy of Fallot (TOF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra- and extracardiac phenotypes. We investigated genotype-phenotype correlation in a large cohort of 230 unselected patients with TOF, in whom we performed karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in patients with TOF and otherwise unexplained mental retardation.
We found pathogenic genetic aberrations in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic TOF (0.9%). One patient showed a polyalanine stretch elongation within TBX1 which was previously reported as variant of unknown significance in a patient with isolated interruption of the aortic arch. We show that this represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation, for the first time linking the latter to congenital heart defects. The cardiac anomalies of this patient fit into the spectrum of 22q11.2 deletion, and were distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with TOF was very suggestive of trisomy 21 and was absent in 22q11.2 deletion.

Abstract

Tetralogy of Fallot (TOF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra- and extracardiac phenotypes. We investigated genotype-phenotype correlation in a large cohort of 230 unselected patients with TOF, in whom we performed karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in patients with TOF and otherwise unexplained mental retardation.
We found pathogenic genetic aberrations in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic TOF (0.9%). One patient showed a polyalanine stretch elongation within TBX1 which was previously reported as variant of unknown significance in a patient with isolated interruption of the aortic arch. We show that this represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation, for the first time linking the latter to congenital heart defects. The cardiac anomalies of this patient fit into the spectrum of 22q11.2 deletion, and were distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with TOF was very suggestive of trisomy 21 and was absent in 22q11.2 deletion.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:May 2010
Deposited On:05 Mar 2010 08:15
Last Modified:05 Apr 2016 13:58
Publisher:BMJ Publishing Group
ISSN:0022-2593
Funders:DFG
Publisher DOI:https://doi.org/10.1136/jmg.2009.070391
PubMed ID:19948535

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