Overt cleft palate phenotype and TBX1 genotype correlations in velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients

Sean B. Herman, Tingwei Guo, Donna M Mcdonald Mcginn, Anna Blonska, Alan L. Shanske, Anne S. Bassett, Eva W C Chow, Mark Bowser, Molly Sheridan, Frits Beemer, Koen Devriendt, Ann Swillen, Jeroen Breckpot, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Courtney Carpenter, Xin Zheng, Jacob Johnson, Jonathan ChungAnne Marie Higgins, Nicole Philip, Tony Simon, Karlene Coleman, Damian Heine-Suner, Jordi Rosell, Wendy Kates, Marcella Devoto, Elaine Zackai, Tao Wang, Robert Shprintzen, Beverly S. Emanuel, Bernice E. Morrow

Research output: Contribution to journalArticle

Abstract

Velo-cardio-facial syndrome/DiGeorge syndrome, also known as 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, with an estimated incidence of 1/2,000-1/4,000 live births. Approximately 9-11% of patients with this disorder have an overt cleft palate (CP), but the genetic factors responsible for CP in the 22q11DS subset are unknown. The TBX1 gene, a member of the T-box transcription factor gene family, lies within the 22q11.2 region that is hemizygous in patients with 22q11DS. Inactivation of one allele of Tbx1 in the mouse does not result in CP, but inactivation of both alleles does. Based on these data, we hypothesized that DNA variants in the remaining allele of TBX1 may confer risk to CP in patients with 22q11DS. To test the hypothesis, we evaluated TBX1 exon sequencing (n=360) and genotyping data (n=737) with respect to presence (n=54) or absence (n=683) of CP in patients with 22q11DS. Two upstream SNPs (rs4819835 and rs5748410) showed individual evidence for association but they were not significant after correction for multiple testing. Associations were not identified between DNA variants and haplotypes in 22q11DS patients with CP. Overall, this study indicates that common DNA variants in TBX1 may be nominally causative for CP in patients with 22q11DS. This raises the possibility that genes elsewhere on the remaining allele of 22q11.2 or in the genome could be relevant.

Original languageEnglish
Pages (from-to)2781-2787
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Volume158 A
Issue number11
DOIs
Publication statusPublished - Nov 2012

Keywords

  • 22q11.2 deletion syndrome
  • Cleft palate
  • Genomic disorder
  • TBX1 sequencing

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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    Herman, S. B., Guo, T., Mcginn, D. M. M., Blonska, A., Shanske, A. L., Bassett, A. S., Chow, E. W. C., Bowser, M., Sheridan, M., Beemer, F., Devriendt, K., Swillen, A., Breckpot, J., Digilio, M. C., Marino, B., Dallapiccola, B., Carpenter, C., Zheng, X., Johnson, J., ... Morrow, B. E. (2012). Overt cleft palate phenotype and TBX1 genotype correlations in velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients. American Journal of Medical Genetics, Part A, 158 A(11), 2781-2787. https://doi.org/10.1002/ajmg.a.35512