Association of tetralogy of Fallot with a distinct region of del22q11.2

Abstract

Congenital heart defects (CHDs) appear in greater frequency among relatives of patients and in individuals with DiGeorge syndrome (DGS) or velo-cardio-facial syndrome (VCFS). A majority of these patients and part of the apparently nonsyndromic CHD patients with conotruncal defects manifest hemizygous deletions within chromosome 22q11.2 (del22q11). We tested myocardial tissues of 31 CHD patients, 21 with tetralogy of Fallot (TOF) and 10 with a double-chamber right ventricle (DCRV). DNA isolated from tissues removed at corrective surgery was analyzed for homo- or heterozygosity of nine polymorphic short tandem repeat (STR) markers along the 22q11.2 region. DNA from the blood of 45 healthy individuals represented the general population. Ten of the 21 TOF patients (48%) showed homozygosity for three or more consecutive markers, indicating deletions of various sizes. No such indication was found for DCRV patients. Heterozygosity for markers D22S1648, D22S941, and D22S944 was lower in the TOF group than in normal controls, defining a minimal critical region (MCR) for the deletion. Our findings support an association between TOF and hemizygosity in 22q11.2, suggesting a distinct region, between markers D22S1638 and COMT, that may harbor TOF susceptibility genes.

Association of 22q11 deletion with isolated congenital heart disease in three Chinese ethnic groups

“…There was no microsatellite marker loci deletion in the 22a11.2 region of five ASD patients. In 2002, Kessler-Icekson et al reported that 48% of TOF patients had homozygosity for three or more consecutive marks, indicating deletions of various sizes [15]. Our incidence of 22q11.2 deletion with TOF was 50%, which is similar to Kessler-Icekson et al's report.…”

“…Previous studies on isolated TOF/PDA indicated the existence of gene haploid loss in the 22q11.2 region [15]. Although most authors did not think there was a relationship between isolated CHD and 22q11.2 deletion [4][5][6][7], our result here is not only consistent with Wilson et al's report that chromosome 22 deletions were detected in isolated familiar CHD [8,9], but also consistent with McElhinney et al's finding that chromosome 22q11 deletion was associated with isolated anomalies of laterality or branching of the aortic arch [10].…”

Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus

“…In general, CTDs are the disorders most commonly associated with the 22q11.2 deletion syndrome [22,23]. Of the study subjects, 20% (7/35) of those with PA/VSD, 5.4% (4/74) with TOF, 33% (1/3) with PTA and 2% (1/51) with DORV were detected to have the 22q11.2 deletion.…”

22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

“…Candidate critical genes for major features of DGS are thought to include HIRA , TBX1 and COMT [McDonaldMcGinn et al, 1999;Lindsay et al, 2001;Kessler-Icekson et al, 2002;Bearden et al, 2004;Prasad et al, 2008;Chen et al, 2014;Ogata et al, 2014]. CRKL is considered a candidate critical gene for the central deletions [Racedo et al, 2015], and MAPK1/ERK2 for the distal type I deletions [Saba-El-Leil et al, 2003;Binétruy et al, 2007;Newbern et al, 2008;Samuels et al, 2008].…”