Genetic Imbalances in Argentinean Patients with Congenital Conotruncal Heart Defects

Abstract

Congenital conotruncal heart defects (CCHD) are a subset of serious congenital heart defects (CHD) of the cardiac outflow tracts or great arteries. Its frequency is estimated in 1/1000 live births, accounting for approximately 10–30% of all CHD cases. Chromosomal abnormalities and copy number variants (CNVs) contribute to the disease risk in patients with syndromic and/or non-syndromic forms. Although largely studied in several populations, their frequencies are barely reported for Latin American countries. The aim of this study was to analyze chromosomal abnormalities, 22q11 deletions, and other genomic imbalances in a group of Argentinean patients with CCHD of unknown etiology. A cohort of 219 patients with isolated CCHD or associated with other major anomalies were referred from different provinces of Argentina. Cytogenetic studies, Multiplex-Ligation-Probe-Amplification (MLPA) and fluorescent in situ hybridization (FISH) analysis were performed. No cytogenetic abnormalities were found. 22q11 deletion was found in 23.5% of the patients from our cohort, 66% only had CHD with no other major anomalies. None of the patients with transposition of the great vessels (TGV) carried the 22q11 deletion. Other 4 clinically relevant CNVs were also observed: a distal low copy repeat (LCR)D-E 22q11 duplication, and 17p13.3, 4q35 and TBX1 deletions. In summary, 25.8% of CCHD patients presented imbalances associated with the disease.

Genetic Analysis Algorithm for the Study of Patients with Multiple Congenital Anomalies and Isolated Congenital Heart Disease

“…We found 22q11 imbalances in 23% of the patients analyzed by MLPA with conotruncal CHD, similar to our previous results [ 28 ]. Although the 22q11 imbalances were most prevalent among patients presenting MCA, 22% of the patients with isolated conotruncal CHD had a 22q11 microdeletion or duplication, similar to other reports [ 15 , 16 , 17 , 89 ].…”

“…MLPA analysis was performed using the SALSA P250-B1 MLPA kit (MRC-Holland, Amsterdam, The Netherlands) as previously described [ 28 ].…”

“…Although largely studied in several populations, the genetic contribution to CA in Latin America is less documented [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Considering their severity and birth prevalence, the aim of this study was to identify the genetic causes in Argentinian patients with MCA and isolated CHD.…”

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

“…Another cohort study found that rs2832616 and rs1943950 SNPs and CNV in RIPK4 and ZBTB21 genes within chromosome 21 in a Down syndrome patient, suggesting multiple gene aberrations [175]. 22q11 deletion, 17p13.3, 4q35, and TBX1 deletions are highly associated with conotruncal defect abnormalities [176] and 3.76 Mb de novo gain of 9q34.2-q34.3 is associated with tetralogy of Fallot with the absence of pulmonary valve [177]. In addition, serious cardiac malformations have been documented due to duplication and deletion in GATA4 and SOX7 genes respectively [178] as well as in NODAL gene [179].…”

Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States

“…Congenital heart defects comprise some of the most common, serious, and clinically important groups/types of birth defects [ 1 , 2 , 3 ]. These defects consist of a heterogenous group of structural heart malformations (i.e., conotruncal heart defects that affect the cardiac outflow tract) that are thought to have at least some shared genetic basis [ 4 , 5 , 6 , 7 ]. Some conotruncal heart defects involve a deviation from the normal position of the origin of the aorta and pulmonary trunk, in which case the great vessels are said to be transposed.…”