Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio-facial/digeorge/22q11.2 deletion syndrome patients

Tingwei Guo, Donna Mcdonald-Mcginn, Anna Blonska, Alan Shanske, Anne S. Bassett, Eva Chow, Mark Bowser, Molly Sheridan, Frits Beemer, Koen Devriendt, Ann Swillen, Jeroen Breckpot, Maria C. Digilio, Bruno Marino, Bruno Dallapiccola, Courtney Carpenter, Xin Zheng, Jacob Johnson, Jonathan Chung, Anne Marie HigginsNicole Philip, Tony J. Simon, Karlene Coleman, Damian Heine-Suner, Jordi Rosell, Wendy Kates, Marcella Devoto, Elizabeth Goldmuntz, Elaine Zackai, Tao Wang, Robert Shprintzen, Beverly Emanuel, Bernice Morrow

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Haploinsufficiency of TBX1, encoding a T-box transcription factor, is largely responsible for the physical malformations in velo-cardio-facial /DiGeorge/22q11.2 deletion syndrome (22q11DS) patients. Cardiovascular malformations in these patients are highly variable, raising the question as to whether DNA variations in the TBX1 locus on the remaining allele of 22q11.2 could be responsible. To test this, a large sample size is needed. The TBX1 gene was sequenced in 360 consecutive 22q11DS patients. Rare and common variations were identified. We did not detect enrichment in rare SNP (single nucleotide polymorphism) number in those with or without a congenital heart defect. One exception was that there was increased number of very rare SNPs between those with normal heart anatomy compared to those with right-sided aortic arch or persistent truncus arteriosus, suggesting potentially protective roles in the SNPs for these phenotype-enrichment groups. Nine common SNPs (minor allele frequency, MAF > 0.05) were chosen and used to genotype the entire cohort of 1,022 22q11DS subjects. We did not find a correlation between common SNPs or haplotypes and cardiovascular phenotype. This work demonstrates that common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome.

Original languageEnglish (US)
Pages (from-to)1278-1289
Number of pages12
JournalHuman mutation
Issue number11
StatePublished - Nov 2011
Externally publishedYes


  • 22q11.2 deletion syndrome
  • Cardiovascular defects
  • Genomic disorder
  • TBX1 sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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