Developmental Mechanisms of Human Congenital Heart Disease

The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel's team at Children's Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.]]>
Inclusion criteria: Individuals that sign an informed consent form for genetic research. Unrelated de-identified individuals (probands) with 22q11.2DS. A clinical diagnosis of 22q11.2DS by a medical professional. Molecular testing or FISH test positive for the presence of a 22q11.2 deletion. There are 4 blocks of low copy repeats that span the region associated with the syndrome, and they are LCR22-A, B, C and D. Those with LCR22A-B, A-C and A-D are included. Existence of an echocardiogram summary report or cardiology report and a diagnosis of a particular defect or presence of normal structures. Both sexes, all races and ethnicities are included. Exclusion criteria: Individuals that do not sign an informed consent form for genetic research. Affected or unaffected relatives of 22q11.2DS cases, are excluded. Subjects with LCR22B-D or C-D or atypical distal deletions to LCR22D on 22q11.2. Subjects with no cardiovascular phenotype information. Cases have a heart or aortic arch defect. Controls have normal structures. Note that arterial branches from the aortic arch are not always identified by echocardiography. Newborns or young infants with a small ventricular septal defect, persistent foramen ovale, patient ductus arteriosus at birth or in early infancy, but that resolved spontaneously are noted but are not criteria for being termed a case. ]]>
1990 - Samples from 22q11.2 deletion syndrome patients treated at Einstein/Montefiore in NY and Children's Hospital of Philadelphia (CHOP) in PA, were collected in separate IRB approved programs. 2008 - International 22q11.2 Consortium began at the 6th International 22q11.2 deletion syndrome conference in Utrecht, 2008. This began a collaboration between >22 independent research sites including Einstein/Montefiore and CHOP. De-identified DNA samples were obtained and Affymetrix 6.0 arrays were performed. A subset of the samples was subjected to WES (dbGaP, phs000987.v1.p1). 2012 - International 22q11.2 Brain and Behavior Consortium began with a focus on identifying genes for schizophrenia. The members of the two consortia are almost identical. Cardiac phenotype data has been obtained for as many DNA samples as possible. MLPA assays were performed on most DNA samples in Dr. Emanuel's lab at CHOP. Most of the samples collected with appropriate neurocognitive and psychiatric information are being subjected to WGS, led by Dr. Steve Warren at Emory University, Atlanta, GA, USA.]]>