title: Overt cleft palate phenotype and TBX1 genotype correlations in velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients.
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.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Sean B
authors.initials: SB
authors.lastname: Herman
authors.forename: Tingwei
authors.initials: T
authors.lastname: Guo
authors.forename: Donna M McDonald
authors.initials: DM
authors.lastname: McGinn
authors.forename: Anna
authors.initials: A
authors.lastname: Blonska
authors.forename: Alan L
authors.initials: AL
authors.lastname: Shanske
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
authors.forename: Eva W C
authors.initials: EW
authors.lastname: Chow
authors.forename: Mark
authors.initials: M
authors.lastname: Bowser
authors.forename: Molly
authors.initials: M
authors.lastname: Sheridan
authors.forename: Frits
authors.initials: F
authors.lastname: Beemer
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: Ann
authors.initials: A
authors.lastname: Swillen
authors.forename: Jeroen
authors.initials: J
authors.lastname: Breckpot
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Digilio
authors.forename: Bruno
authors.initials: B
authors.lastname: Marino
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Courtney
authors.initials: C
authors.lastname: Carpenter
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.forename: Jacob
authors.initials: J
authors.lastname: Johnson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chung
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Higgins
authors.forename: Nicole
authors.initials: N
authors.lastname: Philip
authors.forename: Tony
authors.initials: T
authors.lastname: Simon
authors.forename: Karlene
authors.initials: K
authors.lastname: Coleman
authors.forename: Damian
authors.initials: D
authors.lastname: Heine-Suner
authors.forename: Jordi
authors.initials: J
authors.lastname: Rosell
authors.forename: Wendy
authors.initials: W
authors.lastname: Kates
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Shprintzen
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Emanuel
authors.forename: Bernice E
authors.initials: BE
authors.lastname: Morrow
mesh_terms: D001483:Base Sequence; D002972:Cleft Palate / Q000150:complications* / Q000453:epidemiology / Q000235:genetics*; D004062:DiGeorge Syndrome / Q000150:complications* / Q000235:genetics; D005260:Female; D023061:Gene Order; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D020825:T-Box Domain Proteins / Q000235:genetics*
chemical_list: D020825:T-Box Domain Proteins; C108625:TBX1 protein, human