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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


Griffin, H R; Töpf, A; Glen, E; Zweier, C; Stuart, A G; Parsons, J; Peart, I; Deanfield, J; O'Sullivan, J; Rauch, A; Scambler, P; Burn, J; Cordell, H J; Keavney, B; Goodship, J A (2010). 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. Heart, 96(20):1651-1655.

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.

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.

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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:2010
Deposited On:24 Feb 2011 15:17
Last Modified:05 Apr 2016 14:50
Publisher:BMJ Publishing Group
ISSN:1355-6037
Additional Information:This paper is freely available online under the BMJ Journals unlocked scheme, see http://heart.bmj.com/site/about/unlocked.xhtml
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1136/hrt.2010.200121
PubMed ID:20937753
Permanent URL: https://doi.org/10.5167/uzh-46710

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