Conotruncal Heart Disease Research Articles

Epigenetics of conotruncal congenital heart disease: Protocol for a systematic review and meta-analysis.

Conotruncal congenital heart defects (CTD) are a subset of congenital heart diseases (CHD) that involve structural anomalies of the right, left, or both cardiac outflow tracts. CHD is caused by multifactorial inheritance and changes in the genes or chromosomes. Recently, CHD was found to be due to epigenetic alterations, which are a combination of genetic and other environmental factors. Epigenetics is the study of how a gene's function changes as a result of environmental and behavioral influences. These causative factors can indirectly cause CHD by altering the DNA through epigenetic modifications. This is a protocol for a systematic review and meta-analysis that aims to explore whether the strength of association between various epigenetic changes and CTD types varies by race. Furthermore, to determine and compare the changes in gene expression of each mutation. Our protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. A comprehensive pre-search has been developed in PubMed and PubMed's Medical Subject Headings (MeSH). The final search will be performed in June 2023 in PubMed, Embase, Scopus, Web of Science, Cochrane Library, CIANHL, and PsycInfo, without restrictions on publication years. The Covidence systematic review software will be used for blinded screening and selection. Conflicts will be resolved by a third, independent reviewer. The risk of bias in selected studies will be assessed using the National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The data to be extracted will cover basic information on the included studies, study sample size, number of patients with various types of epigenetic changes, number of patients with various CTD types, measures of association and their 95% confidence interval between each epigenetic change and each CTD. The protocol has been registered with the International Prospero Register of Systematic Review (PROSPERO) [CRD42023377597]. To the best of our knowledge, this protocol outlines the first systematic review and meta-analysis of the epigenetics of CTD. There is a growing body of evidence on epigenetics and its indirect involvement in disease by altering the DNA through epigenetic modifications in the genes associated with the causative factors for CHD. We will conduct a comprehensive and systematic search for literature in the above-mentioned seven core biomedical databases. It is very important to identify population-specific risk factors for CHD, which will have significant creative, custom-made, and effective prevention programs for the future generation.

Oligogenic Architecture of Rare Noncoding Variants Distinguishes 4 Congenital Heart Disease Phenotypes.

Congenital heart disease (CHD) is highly heritable, but the power to identify inherited risk has been limited to analyses of common variants in small cohorts. We performed reimputation of 4 CHD cohorts (n=55 342) to the TOPMed reference panel (freeze 5), permitting meta-analysis of 14 784 017 variants including 6 035 962 rare variants of high imputation quality as validated by whole genome sequencing. Meta-analysis identified 16 novel loci, including 12 rare variants, which displayed moderate or large effect sizes (median odds ratio, 3.02) for 4 separate CHD categories. Analyses of chromatin structure link 13 of the genome-wide significant loci to key genes in cardiac development; rs373447426 (minor allele frequency, 0.003 [odds ratio, 3.37 for Conotruncal heart disease]; P=1.49×10-8) is predicted to disrupt chromatin structure for 2 nearby genes BDH1 and DLG1 involved in Conotruncal development. A lead variant rs189203952 (minor allele frequency, 0.01 [odds ratio, 2.4 for left ventricular outflow tract obstruction]; P=1.46×10-8) is predicted to disrupt the binding sites of 4 transcription factors known to participate in cardiac development in the promoter of SPAG9. A tissue-specific model of chromatin conformation suggests that common variant rs78256848 (minor allele frequency, 0.11 [odds ratio, 1.4 for Conotruncal heart disease]; P=2.6×10-8) physically interacts with NCAM1 (PFDR=1.86×10-27), a neural adhesion molecule acting in cardiac development. Importantly, while each individual malformation displayed substantial heritability (observed h2 ranging from 0.26 for complex malformations to 0.37 for left ventricular outflow tract obstructive disease) the risk for different CHD malformations appeared to be separate, without genetic correlation measured by linkage disequilibrium score regression or regional colocalization. We describe a set of rare noncoding variants conferring significant risk for individual heart malformations which are linked to genes governing cardiac development. These results illustrate that the oligogenic basis of CHD and significant heritability may be linked to rare variants outside protein-coding regions conferring substantial risk for individual categories of cardiac malformation.

Screening Method for 22q11 Deletion Syndrome Involving the Use of TaqMan qPCR for TBX1 in Patients with Conotruncal Congenital Heart Disease

22q11.2 deletion syndrome is a phenotypic spectrum that encompasses DiGeorge syndrome (OMIM: 188400) and velocardiofacial syndrome (OMIM: 192430). It is caused by a 1.5–3.0 Mb hemizygous deletion of locus 22q11.2, which leads to characteristic facies, conotruncal cardiovascular malformations, velopharyngeal insufficiency, T-lymphocyte dysfunction due to thymic aplasia, and parathyroid hypoplasia, and, less frequently, neurological manifestations such as delayed psychomotor development or schizophrenia. This study aimed to describe a screening method for the diagnosis of 22q11.2 deletion syndrome in patients with Conotruncal Congenital Heart Disease (CCHD), using qPCR to detect the copy number of the TBX1 gene in a single DNA sample. A total of 23 patients were included; 21 with a biallelic prediction of the TBX1 copy number gene and 2 with a monoallelic prediction who were suspected to be positive and subjected to MLPA confirmation. One patient (4.34%) with truncus arteriosus CCHD was confirmed to have 22q11.2 deletion syndrome. We propose this approach as a possible newborn screening method for 22q11.2 deletion syndrome in CCHD patients.

Abstract 10063: Implementation of Appropriate Use Criteria for Cardiac Computed Tomography and Magnetic Resonance Imaging in the Follow-Up Care of Patients with Conotruncal Congenital Heart Disease

Introduction: To promote the rational use of cardiovascular imaging in the delivery of high-quality and cost-effective care to patients with congenital heart disease (CHD), the American College of Cardiology developed Appropriate Use Criteria (AUC). We aimed to evaluate the appropriateness of indications for cardiac CT and MRI in patients with conotruncal defects and to identify factors associated with Maybe or Rarely Appropriate (M/R) indications. Methods: Twelve US centers contributed a median of 147 studies performed prior to AUC publication (01/2020) on patients with conotruncal defects. Studies were excluded if the patient did not receive primary cardiac care at the center or were not seen > 5 years prior to study date. To account for the nesting of physicians within center, a hierarchical generalized linear mixed model was used to account for center-level variation with physicians nested within center. Results: Of the 1,753 studies (20% CT, 80% MRI) from 12 centers, 16% (range 4-39%) were rated M/R and 2.4% were unclassifiable (Figure 1). Patients age <1 year accounted for 8.4% of studies. In multivariable analyses, patient- and study-level factors associated with M/R rating included: age <1 year (OR 1.9 [95% CI 1.1-3.4]), truncus arteriosus (vs. TOF, OR 2.2 [95% CI 1.2-4.0]), and CT (vs. MRI, OR 2.5 [95% CI 1.7-3.8]). Center-level factors included: part of an adult hospital (vs. stand-alone children’s, OR 0.8 [95% CI 0.2-0.7]) and annual MRI volume (for every 50 unit increase, OR 0.96 [95% CI 0.92-0.99]. Provider-level factors did not remain significant in the multivariable model. Conclusions: Most cardiac CTs and MRIs ordered for the follow-up care of patients with conotruncal defects were rated Appropriate and nearly all were able to be classified. However, there was significant center-level variation and higher annual MRI volume was independently associated with lower odds of M/R rating. These findings inform future quality improvement initiatives.

KOMMERELL DIVERTICULUM: A RARE BUT POTENTIALLY LIFE THREATENING ANOMALY

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Kommerell diverticulum and aberrant subclavian artery are rare anomalies of the aortic branches in the upper mediastinum. We are presenting a case of a patient incidentally diagnosed with Kommerell diverticulum and aberrant left subclavian artery. CASE PRESENTATION: A 61-year-old male with hypertension and heart failure with preserved ejection fraction, presented to the cardiology clinic after overnight hospitalization for one episode of short-lasting midline chest and left arm pain while resting. He had a history of multiple episodes of non-exertional chest pain and exertional dyspnea, dysphagia and occasional wheezing. Stress test was negative for reversible perfusion defect and showed normal left ventricular ejection fraction. A recently performed transthoracic echocardiogram showed dilated aortic root and possible bicuspid aortic valve. Computed tomography angiogram (CTA) of aorta was performed for further evaluation. CTA aorta revealed a right sided aortic arch and aberrant left subclavian artery with a diverticulum of Kommerell. The patient is being closely followed up outpatient to prevent any potential complications. DISCUSSION: Aberrant left subclavian artery (ALSA) is seen in 0.05-0.1% population and a right aortic arch (aortic arch traversing over the right bronchus) is seen in 0.5% population. These anomalies can be associated with DiGeorge syndrome (deletion of chromosome 22q11.2) and conotruncal congenital heart disease. They can incompletely encircle the trachea and esophagus, creating a partial vascular ring and causing dyspnea, wheezing and dysphagia. In many cases, the ALSA arises from a vascular structure called Kommerell diverticulum (KD), most often derived from a remnant of the fourth aortic arch. KD is similar to the ascending aorta in diameter, and can compress the trachea and esophagus, producing the symptoms mentioned above. It can also cause complications like recurrent pneumonia, aortic dissection or fatal mediastinal hemorrhage from aneurysmal rupture of the diverticulum. CONCLUSIONS: Aneurysms of aberrant subclavian arteries need surgical and/or endovascular resection to decrease mortality. Hence, early diagnosis with close monitoring is crucial in patients with Kommerell diverticulum and aberrant subclavian artery. REFERENCE #1: Adams MT, Wilhelm M, Singh N, Andersen C. Right Aortic Arch With Kommerell Diverticulum: A Rare Cause of Dysphagia. JAMA Otolaryngol Head Neck Surg. 2014;140(6):560-562. doi:10.1001/jamaoto.2014.417 REFERENCE #2: Bhatt TC, Muralidharan CG, Singh G, Jain NK. Kommerell's diverticulum: A rare aortic arch anomaly. Med J Armed Forces India. 2016;72(Suppl 1):S80-S83. doi:10.1016/j.mjafi.2016.09.003 DISCLOSURES: No relevant relationships by surya Aedma, source=Web Response No relevant relationships by Pranav Mahajan, source=Web Response No relevant relationships by Riddhi Upadhyay, source=Web Response No relevant relationships by Karen Wiarda, source=Web Response

Fetal Blood Flow and Genetic Mutations in Conotruncal Congenital Heart Disease.

In congenital heart disease, the presence of structural defects affects blood flow in the heart and circulation. However, because the fetal circulation bypasses the lungs, fetuses with cyanotic heart defects can survive in utero but need prompt intervention to survive after birth. Tetralogy of Fallot and persistent truncus arteriosus are two of the most significant conotruncal heart defects. In both defects, blood access to the lungs is restricted or non-existent, and babies with these critical conditions need intervention right after birth. While there are known genetic mutations that lead to these critical heart defects, early perturbations in blood flow can independently lead to critical heart defects. In this paper, we start by comparing the fetal circulation with the neonatal and adult circulation, and reviewing how altered fetal blood flow can be used as a diagnostic tool to plan interventions. We then look at known factors that lead to tetralogy of Fallot and persistent truncus arteriosus: namely early perturbations in blood flow and mutations within VEGF-related pathways. The interplay between physical and genetic factors means that any one alteration can cause significant disruptions during development and underscore our need to better understand the effects of both blood flow and flow-responsive genes.

Folic acid, periconceptional multivitamin supplementation and pregnancy: modern aspects

Folic acid (vitamin B9) is a water-soluble vitamin, essential for the growth and development of the blood and immune systems. Its deficiency is a significant risk factor for fetal neural tube defects. The widespread implementation of drugs and food supplements containing folic acid in preparation for pregnancy and in its first trimester has significantly reduced the incidence of fetal neural tube defects.According to current recommendations, taking 0.4 mg of folic acid per day is indicated within 6 months before conception and in the first trimester of pregnancy. Taking folic acid at a dosage of 4 mg is indicated for patients with a history of a fetal neural tube defect.There are also other risk factors for developing fetal neural tube defects. These include family history, obesity, malabsorption syndrome, folate cycle gene polymorphisms, smoking, drug use, diabetes mellitus (pre-gestational), and other chronic diseases. Determination of the required dosage of folic acid in these categories of patients still requires discussion and clinical trials. Also, folic acid intake is associated with a decreased risk of esophageal atresia, conotruncal heart disease, cleft palate, urinary tract malformations, and omphalocele, reduces the incidence of some behavioral anomalies, in particular, hyperactivity, the need for planning a pregnancy.

Blood flow simulations in the pulmonary bifurcation in relation to adult patients with repaired tetralogy of Fallot

Understanding the haemodynamic environment of the pulmonary bifurcation is important in adults with repaired conotruncal congenital heart disease. In these patients, dysfunction of the pulmonary valve and narrowing of the branch pulmonary arteries are common and can have serious clinical consequences. The aim of this study was to numerically investigate the underlying blood flow characteristics in the pulmonary trunk under a range of simplified conditions. For that, an in-depth analysis was conducted in idealised two-dimensional geometries that facilitate parametric investigation of healthy and abnormal conditions. Subtle variations in morphology influenced the haemodynamic environment and wall shear stress distribution. The pressure in the left pulmonary artery was generally higher than that in the right and main arteries, but was markedly reduced in the presence of a local stenosis. Different downstream pressure conditions altered the branch flow ratio, from 50:50% to more realistic 60:40% ratios in the right and left pulmonary artery, respectively. Despite some simplifications, this study highlights some previously undocumented aspects of the flow in bifurcating geometries, by clarifying the role of the stagnation point location on wall shear stress and differential branch pressures. In addition, measurements of the mean pressure ratios in the pulmonary bifurcation are discussed in the context of a new haemodynamic index which could potentially contribute to the assessment of left pulmonary artery stenosis in tetralogy of Fallot patients. Further studies are required to confirm the results in patient-specific models with personalised physiological flow conditions.

Initial validation of the diagnostic performance of Thymic-Thoracic Ratio as a marker of conotruncal abnormalities and for prediction of surgical prognosis in fetuses without 22q11.2 deletion

Aim The present study aimed to perform an initial validation of the Thymic-Thoracic Ratio as a sonographic marker of conotruncal defects in non-syndromic fetuses and to assess the possible correlation between the grade of thymic hypoplasia and the severity of conotruncal defects. Methods The study was conducted between January and June 2018 on singleton pregnant women who underwent fetal echocardiography at our institution. Fetuses with a diagnosis of conotruncal defects without 22q11.2 deletion composed the study group, while healthy appropriate for gestational age fetuses composed the control group. The Thymic-Thoracic Ratio was measured in all included fetuses and compared between the study and control group. A ROC curve analysis to evaluate the diagnostic performance of Thymic-Thoracic Ratio toward the diagnosis of conotruncal defects was performed, with determination of sensitivity, specificity, PPV, NPV, positive likelihood ratio, and negative likelihood ratio. The severity of conotruncal defects was defined with the Aristotle score in each newborn who underwent a surgical operation. The correlation between Thymic-Thoracic Ratio and Aristotle score was assessed. Results During the study period, 23 fetuses with conotruncal defects without 22q11.2 deletion constituted the study group, and 67 healthy appropriate for gestational age fetuses were included in the control group. The T-T ratio of the study group was significantly lower than the control group (0.32 ± 0.08 vs. 0.41 ± 0.08, p < .001). The ROC curve analysis showed an AUC of 0.80 (95% CI, 0.71–0.89, p < .001) and a T-T ratio cutoff value of 0.35 for the identification of a CTD, with a sensibility of 73.9% (95% CI: 51.6–89.8%), a specificity of 79.1% (95% CI: 67.4–88.1%) a PPV of 54.8% (95% CI: 41.8–67.3%), a NPV of 89.8% (95% CI: 81.5–94.7), a positive likelihood ratio of 3.54 (95% CI 2.09–5.98), and a negative likelihood ratio of 0.33 (95% CI 0.16–0.66). A negative correlation between Aristotle score and T-T ratio was found, with a Kendall-Tau coefficient of −0.41, p = .04. Conclusion T-T ratio measurement could be useful to identify fetuses at higher risk of conotruncal heart diseases, even without chromosomic deletion, with a cutoff of 0.35. Since a lower T-T ratio seems to be related to a worse surgical neonatal prognosis, it could be possible to provide effective counseling and refer patients to high-specialized centers for fetal echocardiography and cardiac surgery.

P01.02: Frequency of 22q11 microdeletion syndrome in fetuses with conotruncal heart disease

P01.02: Frequency of 22q11 microdeletion syndrome in fetuses with conotruncal heart disease

The possibilities of computed tomography heart-axis-oriented multiplanar reformations in diagnostics of common arterial trunk

The possibility of using multiplanar reformations oriented on the axis of heart in diagnosing the common arterial trunk with X-ray computed tomography is substantiated. Examination data of 140 patients aged 1-19 days of life, 3030-3890 g body weight with conotruncal congenital heart diseases was analyzed, and common arterial trunk was detected in 7 patients (4 - boys, 3 - girls). In 5 (72%) patients, it developed mainly from the morphological right ventricle, 1 (14%) - completely from the morphologically right ventricle, and 1 more (14%) - evenly located above the ventricles. In four (57%) cases, the trunk valve had three leaflets, in two (28,5%) cases - two, in one (14,5%) case - four. All the patients had mitral-semilunar fibrous prolongation, intraventricular septal defects, doubled coronary arteries system, and the pulmonary arteries had their origin from ascendant part of common trunk. Pulmonary arteries had also their own common trunk in 4 (57%) cases, separate estuary in 3 (43%) cases. Aortic arc abnormalities included dextral aortic arc (2 cases), discontinuity of aortic arc (1 case), discontinuity of fourth aortic arc with persistence of fifth left aortic arc (2 cases). In general, computed tomographic angiocardiography heart-axis-oriented multiplanar reformations permit full and correct assessment of heart and main vessels, which is important for surgical treatment planning in congenital heart diseases.

Association Between Tetralogy of Fallot and Tracheobronchial Branching Abnormalities: A New Clue for Pathogenesis?

BackgroundIn our practice, we noticed an increased frequency of tracheobronchial branching abnormalities (TBAs) in patients with tetralogy of Fallot (ToF). This study aimed to determine whether an association exists between congenital TBAs and ToF with or without pulmonary atresia.Methods and ResultsThe frequency of TBAs on chest computed tomography was assessed in 55 patients with ToF without pulmonary atresia, 34 patients with ToF with pulmonary arteria, and 100 control patients. We then looked for a possible association between TBAs and pulmonary artery branch hypoplasia, the presence of major aortopulmonary collateral arteries, and the presence of the chromosome 22q11 deletion. TBAs were significantly more frequent in patients with ToF with or without pulmonary atresia than in the control group (any TBAs, 21% versus 2% [P<0.001]; bronchial situs anomalies, 6% versus 0% [P=0.002]; right tracheal bronchus, 4% versus 0% [P=0.04]; left eparterial bronchus, 8% versus 0% [P=0.005]); and tended to be more frequent in those with ToF without pulmonary atresia than in those with ToF with pulmonary atresia (any TBAs, 27% versus 12% [P=0.11]; left eparterial bronchus, 13% versus 0% [P=0.04]). TBAs were readily multiple (8 patients of 19 with TBA) and concerned essentially the upper lobes. TBAs were not associated with pulmonary branch hypoplasia, major aortopulmonary collateral arteries, or the chromosome 22q11 deletion.ConclusionsWe demonstrated a significantly increased frequency of tracheobronchial abnormalities in patients with ToF with or without pulmonary atresia compared with a control group. These results suggest an interaction between abnormalities in conotruncal septation and tracheobronchial branching and may provide a new clue to the pathogenesis of conotruncal heart diseases.

De novo large rare copy-number variations contribute to conotruncal heart disease in Chinese patients.

Conotruncal heart anomalies (CTDs) are particularly prevalent congenital heart diseases (CHD) in Hong Kong. We surveyed large (>500 kb), rare (<1% frequency in controls) copy-number variations (CNVs) in Chinese patients with CTDs to identify potentially disease-causing variations. Adults who tested negative for 22q11.2 deletions were recruited from the adult CHD clinic in Hong Kong. Using a stringent calling criteria, high-confidence CNV calls were obtained, and a large control set comprising 3,987 Caucasian and 1,945 Singapore Chinese subjects was used to identify rare CNVs. Ten large rare CNVs were identified, and 3 in 108 individuals were confirmed to harbour de novo CNVs. All three patients were syndromic with a more complex phenotype, and each of these CNVs overlapped regions likely to be important in CHD. One was a 611 kb deletion at 17p13.3, telomeric to the Miller–Dieker syndrome (MDS) critical region, overlapping the NXN gene. Another was a 5 Mb deletion at 13q33.3, within a previously described critical region for CHD. A third CNV, previously unreported, was a large duplication at 2q22.3 overlapping the ZEB2 gene. The commonly reported 1q21.1 recurrent duplication was not observed in this Chinese cohort. We provide detailed phenotypic and genotypic descriptions of large rare genic CNVs that may represent CHD loci in the East Asian population. Larger samples of Chinese origin will be required to determine whether the genome-wide distribution differs from that found in predominantly European CHD cohorts.

Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families.

We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested. In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)). Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.Genet Med 18 9, 914-923.

Acute dystonia in a patient with 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (di George syndrome) is one of the most prevalent genetic disorders. The clinical features of the syndrome are distinct facial appearance, velopharyngeal insufficiency, conotruncal heart disease, parathyroid and immune dysfunction; however, little is known about possible neurodegenerative diseases. We describe the case of an 18-year old patient suffering from 22q11.2 deletion syndrome. Since adolescence, he presented with behavioral disorders, recommended treatment with 2 mg aloperidin and he presented cervical dystonia and emergence of torticollis and trunk dystonia. Antipsychotic medications either accelerate or reveal dys-tonic symptoms.

Exclusion of chromosomal abnormalities and microdeletions 22q11 and 10p13 in algerian patients with isolated conotruncal malformation

The chromosomal abnormalities of number and structure or the 22q11.2 and 10p13-14 microdeletions are considered the main causes of congenital heart disease. In our best knowledge, cytogenetics studies on congenital heart diseases (CHD) have not been performed in Algeria. In this study, we will screen for chromosomal abnormalities and microdeletions of 22q11.2 and 10p13 in a cohort of Algerian patients. G-banded by trypsin Giemsa (GTG) and Fluorescent In Situ Hybridization (FISH) techniques have been performed to screen for chromosomal abnormalities and a critical regions 22q11.2 and 10p13-14 respectively in seventy patients with non syndromic congenital heart. GTG technique visualized no chromosomal abnormalities of number and structure in our patients. Moreover, FISH visualizing critical regions 22q11.2 and 10p13-14 respectively did not detect any microdeletion in the chromosomes 10 and 22 respectively of our patients. Our study could suggest that congenital heart defects observed in Algerian patients are not due to chromosomal abnormalities of number and structure nor the 22q11.2 and 10p13-14 microdeletions. For the fist time, we report here cytogenetics analysis of chromosomal abnormalities and the 22q11.2 and 10p13-14 microdeletions in Algerian patients with congenital heart disease. Genetic testing for screening for deletion 22q11.2 and 10p13-14 is not indicated in all patients with isolated conotruncal defects. In addition, conotruncal heart diseases have a multifactorial background like consanguinity and recessive mutations in some genes involved in cardiac morphogenesis. A genetic study to screen for the role of consanguineous marriages and some genes linked to CHD in Algerian population is on going. This study will focus also on health education for the families at risk about the importance of pre-marital genetic counseling.

Association of MTHFR A1298C polymorphism with conotruncal heart disease.

Congenital heart diseases are common congenital anomalies with 1% prevalence worldwide and are associated with significant childhood morbidity and mortality. Among a wide range of aetiologically heterogeneous conditions, conotruncal anomalies account for approximately one-third of all congenital heart defects. The aetiology of conotruncal heart diseases is complex, with both environmental and genetic causes. Hyperhomocysteinaemia, which is often accompanied by the defects of folic acid metabolism, is known to cause conotruncal heart anomalies. In this study, we have evaluated three polymorphisms in the following two hyperhomocysteinaemia-related genes: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and nicotinamide N-methyl transferase (NNMT rs694539) in 79 children with conotruncal heart disease and 99 children without conotruncal heart disease. Genotype distribution of the MTHFR A1298C polymorphism showed a statistically significant difference between the two groups. In the case group, AC and CC genotypes were higher than the control group (p<0.05). We have found that MTHFR A1298C polymorphism is associated with conotruncal heart disease; C allele (p=0.028), AC (OR[95% CI]=2.48[1.24-4.95], p=0.010), CC (OR[95% CI]=3.01[1.16-7.83], p=0.023), and AC+CC (OR[95% CI]=2.60[1.36-4.99], p=0.004) genotypes are more frequent in the patient group. Genotype distributions of the MTHFR C677T and NNMT rs694539 polymorphisms were similar in the two groups when evaluated separately and also according to the dominant genetic model (p>0.05). Our results suggest that MTHFR 1298C allele is a risk factor for conotruncal heart disease.

Array comparative genomic hybridisation testing in CHD.

CHD is the leading cause of mortality due to birth defects. Array comparative genomic hybridisation (aCGH) detects submicroscopic copy number changes and may improve identification of the genetic basis of CHD. This is a retrospective analysis of 1252 patients from a regional referral centre who had undergone aCGH. Of the patients, 173 had CHD. A whole-genome custom-designed oligonucleotide array with >44,000 probes was used to detect copy number changes. Of the 1252 patients, 335 (26.76%) had abnormal aCGH results. Of the 173 patients with CHD, 50 (28.9%) had abnormal aCGH results versus 284 (26.3%) of 1079 non-cardiac patients. There were six patients with CHD who had well-described syndromes such as Wolf-Hirschhorn, trisomy 13, DiGeorge, and Williams. Of the patients with CHD, those with left-sided heart disease had the highest proportion (14/31; 45.13%) of abnormal aCGH results, followed by those with conotruncal heart disease (10/29; 34.48%), endocardial cushion defects (13/50; 26%), complex/other heart disease (12/52; 23.08%), and patent ductus arteriosus (1/11; 9.09%). Patients with CHD are at a substantial risk of having microdeletions and microduplications. The incidence of abnormalities on aCGH analysis is higher than identified with karyotype, and identification of copy number changes may help identify the genetic basis of the specific heart defects. However, aCGH may not have a significant diagnostic yield in those with isolated CHD. Further research using larger data sets may help identify candidate genes associated with CHD.

Prenatal Diagnosis of Digeorge Syndrome

Velocardiofacial syndrome, conotruncal congenital heart disease and DiGeorge syndrome present different aspects of the same clinical situation, but congenital heart disease is common to them all [1]. Other defects found in these syndromes include abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia. A deletion at chromosome 22q11 is the second most common chromosomal defect detected in patients with congenital heart disease. Although familial inheritance occurs, most cases are sporadic [2]. A patient aged 29 years, gravida 2, para 1, presented to our outpatient clinic with an initial diagnosis of polyhydramnios at the 33 rd week of gestation. Her medical history revealed that her first delivery was at term by cesarean section, but the baby died in infancy of cyanotic heart disease, diffuse bronchopulmonary disease, and infection. Postmortem genetic investigation revealed that the neonate had a 22q11 deletion, with associated cardiovascular anomalies. The parents were genetically normal. Obstetric examination determined that the patient was at 33 weeks of gestation, and fetal biometric measurements suggested a gestational age of 31–32 weeks. The amniotic index was 18 cm and mild polyhydramnios was detected. Systematic ultrasonographic investigation revealed a ventricular septal defect, a secundum-type atrial septal defect, pulmonary atresia, and an anomaly of the overriding aorta. These findings were interpreted as components of tetralogy of Fallot (TOF). The patient had not attended the hospital for prenatal screening during her second trimester. Cordocentesis was performed for prenatal diagnosis. The cytogenetic analysis was evaluated as normal, but considering the clinical findings and the patient’s prior history, locus-specific fluorescence in situ hybridization (FISH) was planned to detect possible DiGeorge syndrome. A Tuple1-Hira

Revisión de 22 casos de deleción 22q11.2: espectro fenotípico

The 22q11.2 deletion syndrome is a contiguous gene deletion syndrome with an incidence rate of 1/4,000-6,000 live births. The most specific clinical features are: congenital conotruncal heart diseases, palate anomalies, hypocalcaemia, immunity and learning problems, and a characteristic facial phenotype. The objective of this work is to review the presenting phenotype and clinical features of children with 22q11.2 deletion syndrome as a guide for early diagnosis. Retrospective study of 22 patients with 22q11.2 deletion syndrome diagnosed at our hospital in the time period 2004-2007. Variables analyzed: incidence, sex, age at diagnosis, presenting phenotype, clinical features, positive family history, mortality and natural history. From a total of 22 patients, 63 % were males, and the median age at diagnosis was of 4.5 years. Presenting pheno-type: congenital heart disease, milestones delay, velopharyngeal incompetence, hypocalcaemia, and mental retardation/psychiatric disturbances. congenital heart disease (84 %), velopharyngeal incompetence (47 %), milestones delay and learning disabilities (79 %). All of the deletions were de novo, except in one case where the deletion was present as mosaicism in the father. Three patients died, due to congenital heart disease. Clinical expression is widely variable, although a characteristic phenotype exists. Patients with heart disease are diagnosed earlier than other patients with unusual presenting phenotype such as congenital dysphagia. It is important to recognize less common phenotypes at early ages in order to provide multidisciplinary monitoring and accurate genetic counselling.