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BMJ Publishing Group, Heart, 20(96), p. 1651-1655, 2010

DOI: 10.1136/hrt.2010.200121

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Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants

Journal article published in 2010 by Helen R. Griffin ORCID, Ana Töpf, Elise Glen, Christiane Zweier, A. Graham Stuart, A. Graham Stuart, Jonathan Parsons, Ian Peart, John Deanfield, John O'Sullivan, Anita Rauch, Peter Scambler, John Burn, Heather J. Cordell, Bernard Keavney and other authors.
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Abstract

BACKGROUND: Tetralogy of Fallot (TOF) is common in individuals with hemizygous deletions of chromosome 22q11.2 that remove the cardiac transcription factor TBX1. OBJECTIVE: To assess the contribution of common and rare TBX1 genetic variants to TOF. DESIGN: Rare TBX1 variants were sought by resequencing coding exons and splice-site boundaries. Common TBX1 variants were investigated by genotyping 20 haplotype-tagging SNPs capturing all the common variations present at the locus. Association analysis was performed using the program UNPHASED. PATIENTS: TBX1 exons were sequenced in 93 patients with non-syndromic TOF. Single nucleotide polymorphism analysis was performed in 356 patients with TOF, their parents and healthy controls. RESULTS: Three novel variants not present in 1000 chromosomes from healthy ethnically matched controls were identified. One of these variants, an in-frame 57 base-pair deletion in the third exon which removed 19 evolutionarily conserved residues, decreased transcriptional activity by 40% in a dual luciferase assay (p=0.008). Protein expression studies demonstrated that this mutation affected TBX1 protein stability. After correction for multiple comparisons, no significant associations between common genetic variants and TOF susceptibility were found. CONCLUSION: This study demonstrates that rare TBX1 variants with functional consequences are present in a small proportion of non-syndromic TOF.