Overt cleft palate phenotype andTBX1genotype 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.

Retinoic acid inhibits histone methyltransferase Whsc1 during palatogenesis

“…Furthermore, syndromes such as Wolf-Hirschhorn syndrome, DiGeorge syndrome and Pilotto syndrome exhibit both cleft palate and heart defects [2,18,35]. These facts imply that there might be a mutual signaling pathway involved in both palatogenesis and cardiogenesis.…”

Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development

“…Beyond these core features, several additional anomalies have been associated with 22q11DS in recent studies of a small number of fetuses with 22q11 deletions (Besseau-Ayasse et al, 2014; Noel et al, 2014) as well as in 22q11DS patients after birth; albeit at lower frequency than the “core” clinical phenotypes (Cheung et al, 2014; Guo et al, 2011b; Herman et al, 2012; Schneider et al, 2014). The anomalies recognized in fetuses, some of which may contribute to pre-natal demise, include regional dysmorphology of the developing forebrain including arhinen-cephaly—apparent absence of the olfactory bulbs and related forebrain regions (Noel et al, 2014).…”

“…Heterozygous Tbx1 mice do not have any palatal phenotypes (Jerome and Papaioannou, 2001; Liao et al, 2004). In 22q11DS patients, it does not appear likely that the subset of deleted individuals with cleft palate have additional mutations in the remaining copy of TBX1 (Herman et al, 2012). Furthermore, there is no correlation between cleft palate and cardiovascular defects in 22q11DS patients (Friedman et al, 2011), which would be expected if reduced TBX1 were the primary cause of cleft palate in the syndrome.…”

Implications of COMT long-range interactions on the phenotypic variability of 22q11.2 deletion syndrome

“…Thus far, SNP analyses of TBX1 in humans have failed to identify positive associations with the 22q11DS cardiac or cleft palate phenotypes. 19,20 Catechol-O-methyltransferase (COMT ), also deleted in 22q11DS, functions in degrading catecholamines and thus is a candidate for many neurological 22q11DS phenotypes. A valine-to-methionine substitution at codon 158 (COMT Val158Met) results in a form of COMT with decreased enzymatic activity; the presence of this allele in the non-deleted chromosome may further enhance the effects of COMT haploinsufficiency caused by the deletion.…”