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Title: Phenotype-Specific Effect of Chromosome 1q21.1 Rearrangements and GJA5 Duplications in 2436 Congenital Heart Disease Patients and 6760 Controls
Authors: Soemedi, Rachel ×
Topf, Ana
Wilson, Ian J
Darlay, Rebecca
Rahman, Thahira
Glen, Elise
Hall, Darroch
Huang, Ni
Bentham, Jamie
Bhattacharya, Shoumo
Cosgrove, Catherine
Brook, J David
Granados-Riveron, Javier
Setchfield, Kerry
Bulock, Frances
Thornborough, Chris
Devriendt, Koenraad
Breckpot, Jeroen
Hofbeck, Michael
Lathrop, Mark
Rauch, Anita
Blue, Gillian M
Winlaw, David S
Hurles, Matthew
Santibanez-Koref, Mauro
Cordell, Heather J
Goodship, Judith A
Keavney, Bernard D #
Issue Date: Apr-2012
Publisher: IRL Press
Series Title: Human Molecular Genetics vol:21 issue:7 pages:1513-1520
Abstract: Recurrent rearrangements of chromosome 1q21.1 that occur via non-allelic homologous recombination (NAHR) have been associated with variable phenotypes exhibiting incomplete penetrance, including congenital heart disease (CHD). However, the gene or genes within the ~1Mb critical region responsible for each of the associated phenotypes remains unknown. We examined the 1q21.1 locus in 948 patients with tetralogy of Fallot (TOF), 1488 patients with other forms of CHD and 6760 ethnically-matched controls using SNP genotyping arrays (Illumina 660W and Affymetrix 6.0) and multiplex ligation-dependent probe amplification (MLPA). We found that duplication of 1q21.1 was more common in cases of TOF than in controls (OR 30.9 [95% CI 8.9-107.6]; p=2.2x10(-7)), but deletion was not. By contrast, deletion of 1q21.1 was more common in cases of non-TOF CHD than in controls (OR 5.5 [95% CI 1.4-22.0]; p=0.04) while duplication was not. We also detected rare (N=3) 100-200kb duplications within the critical region of 1q21.1 in cases of TOF. These small duplications encompassed a single gene in common, GJA5, and were enriched in cases of TOF in comparison to controls (OR=10.7 [95% CI 1.8-64.3], p=0.01]. These findings show that duplication and deletion at chromosome 1q21.1 exhibit a degree of phenotypic specificity in CHD, and implicate GJA5 as the gene responsible for the CHD phenotypes observed with copy number imbalances at this locus.
URI: 
ISSN: 0964-6906
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Genetics of Human Development
× corresponding author
# (joint) last author

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