Deletion 22q11 and isolated congenital heart disease

The potential for selection bias is a concern in any case-control study. Cases and controls should be representative of the respective diseased and nondiseased persons in a well delineated target population. Even with representative cases and controls, if there is a high (or differential) nonparticipation rate among (or between) cases and controls, selection bias may be introduced. Case-control studies offer an efficient observational analytic design, but they also carry a high potential for the introduction of bias.     

Complex congenital heart disease in unaffected relatives of adults with 22q11.2 deletion syndrome

The 22.q11.2 deletion syndrome (22q11DS) is a common genetic condition associated with 22q11.2 microdeletions and classically has included congenital heart disease (CHD) as a part of the variable expression. Some evidence has shown that relatives of those with 22q11DS might be at an increased risk of CHD in the absence of 22q11.2 deletions. We obtained a detailed family history of CHD in the first- to third-degree relatives (n = 2,639) of 104 adult probands with 22q11DS. We compared the prevalence of CHD in the relatives without 22q11.2 deletions to the published general population prevalence. We also investigated the effect of CHD in the probands on prevalence of CHD in the relatives. Of the 104 probands with 22q11DS, 14 (13.5%) had 17 relatives (17 of 2,639, 0.6%) with CHD. Of 66 probands with CHD, 15 (0.9%) of their 1,663 relatives had CHD, a significantly greater prevalence than that for the relatives of probands without CHD (0.2%, 2 of 976, p = 0.041, odds ratio 4.43, 95% confidence interval 1.03 to 40.00). In relatives of probands with CHD, the prevalence of those with severe CHD (0.36%) was significantly elevated compared to population expectations (0.061%, p = 0.007, odds ratio 5.88, 95% confidence interval 2.16 to 12.85). In conclusion, these results support a heritable susceptibility to CHD in families of probands with 22q11DS, in addition to that imparted by microdeletion 22q11.2. The occurrence of CHD in relatives might be related to the expression of CHD in the proband with 22q11DS. These findings have potential implications for the genetic counseling of families of those with 22q11DS and support the notion that interacting genetic variants might contribute to the variable expression of 22q11DS.     

22q11微缺失综合征与先天性心脏病的关系

目的 探讨22q11微缺失综合征与先天性心脏病的关系.方法 应用荧光原位杂交(FISH) 技术,对207例不同表型的临床疑似患者的外周血标本进行22q11微缺失的检测.分析22q11微缺失综合征患者的超声心动图特征,并对部分复杂先天性心脏病患者行心导管检查.结果 共确诊22q11微缺失综合征患者39例.22q11微缺失综合征的患病率在非综合征性先天性心脏病患者中为1.6%,在综合征性先天性心脏病患者中为53.0%,在无先天性心脏病的疑似患者中则为3.8%.先天性心脏病在22q11微缺失综合征和非22q11微缺失综合征患者中的比例分别为94.9%和54.2%(P＜0.01),综合征性先天性心脏病在22q11微缺失综合征和非22q11微缺失综合征患者中的比例分别为89.7%和18.5%(P＜0.01).在22q11微缺失综合征患者中,先天性心脏病以法洛四联征最多见,心外异常则以面容异常、学习困难和生长发育落后多见.结论 22q11微缺失综合征与先天性心脏病有关.

Abstract：

Objective To investigate the relationship between 22q11 microdeletion syndrome and congenital heart disease. Methods Clinical screening assessment and genetic testing using standard fluorescence in-situ hybridization (FISH) were applied in 207 subjects suspected for 22q11 microdeletion syndrome. Patients with 22q11 microdeletion syndrome were examined by echocardiography, patients with complicated congenital heart disease were examined further by cardiac catheterization. Results 22q11 microdeletion syndrome was detected in 39 subjects. The incidence of 22q11 microdeletion syndrome was 1.6% in suspects with simple congenital heart disease without extracardiac manifestations, 53.0% in suspects with congenital heart disease combined with at least two extracardiac manifestations, 3.8% in suspects without congenital heart disease.The incidence of congenital heart disease in 22q11 microdeletion syndrome patient and non 22q11 microdeletion syndrome patient was 94.9% and 54.2%(P<0.01). The incidence of congenital heart disease combined with at least two extracardiac manifestations in 22q11 microdeletion syndrome patient and non 22q11 microdeletion syndrome patient was 89.7% and 18.5%(P＜0.01).In 22q11 microdeletion syndrome patients, Tetralogy of Fallot was the most common type of congenital heart disease. Dysmorphic faces, learning difficulties and retarded physical development were the most common extracardiac manifestations of the congenital heart disease patients. Conclusion 22q11 microdeletion syndrome is related to congenital heart disease.     

Association of chromosome 22q11 deletion with isolated anomalies of aortic arch laterality and branching

OBJECTIVES

The purpose of this study was to determine the frequency of chromosome 22q11 deletions in patients with isolated anomalies of the aortic arch and its branches.

BACKGROUND

Chromosome 22q11 deletions are often present in patients with certain forms of congenital cardiovascular disease, including tetralogy of Fallot, truncus arteriosus and interruption of the aortic arch. Among patients with these anomalies, chromosome 22q11 deletion is more common in those with abnormal aortic arch laterality or branching.

METHODS

We studied 66 patients with isolated anomalies of the aortic arch and no associated intracardiac defects for deletions within chromosome 22q11, using fluorescence in situ hybridization with the cosmid probe N25 (D22S75). Arch anomalies included: double aortic arch (n = 22); right aortic arch with aberrant left subclavian artery (n = 28); right aortic arch with mirror-image branching and a vascular ring formed by a left-sided ductus from the descending aorta (n = 5); right aortic arch with mirror-image branching and no vascular ring (n = 4); and left aortic arch with aberrant right subclavian artery (n = 7). In addition, four patients had a cervical aortic arch, four had aortic coarctation and six had hypoplasia/atresia of the proximal pulmonary arteries.

RESULTS

Chromosome 22q11 deletions were found in 16 patients (24%) across the full spectrum of anomalies studied. Among the morphologic variables analyzed, only hypoplasia/atresia of the proximal pulmonary arteries correlated with the deletion (p = 0.03). Among patients with a double arch, the frequency of chromosome 22q11 deletion was higher in those with an atretic minor arch than it was in those with a patent minor arch (p = 0.02).

CONCLUSIONS

Chromosome 22q11 deletion is associated with isolated anomalies of laterality or branching of the aortic arch in 24% of cases in our series. These findings should alert the clinician to consider deletion screening in patients with isolated anomalies of the aortic arch.     

DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin.

DiGeorge syndrome was diagnosed in an infant who had an interrupted aortic arch, hypoparathyroidism, and low T lymphocyte numbers. Two siblings had heart defects that are not commonly described in DiGeorge syndrome (a membranous ventricular septal defect and coarctation of the aorta respectively). These siblings did not have evidence of thymic dysfunction or hypoparathyroidism. Chromosome analysis showed that the mother, whose cardiovascular examination was normal, and her three offspring with heart defects had a 22q11 interstitial deletion, which was confirmed by molecular analysis. This family suggests that 22q11 deletions can cause apparently isolated heart defects and that the range of these defects may be wider than previously recognised. Once the genes that are deleted in this family are characterised they will be useful candidate genes in the investigation of isolated cardiac malformations.     

DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin.

DiGeorge syndrome was diagnosed in an infant who had an interrupted aortic arch, hypoparathyroidism, and low T lymphocyte numbers. Two siblings had heart defects that are not commonly described in DiGeorge syndrome (a membranous ventricular septal defect and coarctation of the aorta respectively). These siblings did not have evidence of thymic dysfunction or hypoparathyroidism. Chromosome analysis showed that the mother, whose cardiovascular examination was normal, and her three offspring with heart defects had a 22q11 interstitial deletion, which was confirmed by molecular analysis. This family suggests that 22q11 deletions can cause apparently isolated heart defects and that the range of these defects may be wider than previously recognised. Once the genes that are deleted in this family are characterised they will be useful candidate genes in the investigation of isolated cardiac malformations.     

Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease

Congenital heart disease (CHD), comprising structural or functional abnormalities present at birth, is the most common birth defect in humans. Reduced expression of connexin40 (Cx40) has been found in association with atrial fibrillation, and deletion of Cx40 in a mouse model causes various structural heart abnormalities in 18% of heterozygotes. We screened 505 unrelated CHD cases for deletions or duplications of the Cx40 gene (GJA5) by real-time quantitative PCR, in order to determine whether altered copy number of this gene may be associated with a cardiac phenotype in humans. Dosage of Cx40 flanking genes (ACPL1 and Cx50 gene, GJA8) was determined by real-time PCR for all apparent positive cases. In total, 3 cases were found to carry deletions on chromosome 1q21.1 spanning ACPL1, Cx40, and Cx50 genes. Absence of heterozygosity was observed in all 3 index cases over a 1.5- to 3-Mb region. Samples from the parents of two cases were obtained, and microsatellites across 1q21.1 were genotyped. One of the apparently unaffected parents was found to carry this deletion. All 3 index cases presented with obstruction of the aortic arch as the common structural cardiac malformation, and had no consistent dysmorphic features. Genotyping of 520 unrelated normal controls for this deletion was negative. We hypothesize that this 1q21.1 multigene deletion is associated with a range of cardiac defects, with anomalies of the aortic arch being a particular feature.     

Velopharyngeal incompetence and chromosome 22q11 deletion

Chromosome 22q11 deletion gives rise to various phenotypes, including cardiac malformations, velopharyngeal abnormalities, absent thymus, and neurological defects. We assessed, in a prospective study, chromosome 22q11 deletion in 50 of 144 patients with velopharyngeal incompetence in the absence of overt clefting. 18 (12.5% of the whole cohort and 36% of patients tested for the deletion) had the 22q11 deletion. This frequency differs from an estimated population prevalence of 0.025% and suggests a need for screening for the 22q11 deletion in these patients.     

Airway compression by major aortopulmonary collaterals with 22q11 deletion

Hypoxic choking episodes due to airway obstruction occurred frequently from 4 months of age in a boy with 22q11 deletion, pulmonary atresia, ventricular septal defect, absent central pulmonary artery, tracheobronchomalacia, and an aberrant right tracheal bronchus. The tracheobronchial tree was compressed by a posteriorly displaced ascending aorta and right aortic arch with aberrant left subclavian artery and major aortopulmonary collateral arteries. Single-stage unifocalization and intracardiac repair plus aortopexy at 8 months resulted in resolution of the respiratory distress and heart failure.     

Pseudopulmonary artery sling in a 22q11 deletion newborn with tetralogy of Fallot and isolated left subclavian artery

We report an interest and mystifying cardiovascular imaging in a 22q11 deletion neonate with rare congenital heart defects, including anomalous origin of the left pulmonary artery arising from the right pulmonary artery and in front of the trachea, called pseudo-pulmonary artery sling, combined with isolated left subclavian artery confirmed by multidetector row computed tomography.     

Epidemiology of congestive heart failure in three ethnic groups

Congestive heart failure (CHF) is a leading cause of morbidity, disability, and mortality in old age, but little is known about the epidemiology of this condition in free-living minority populations. To determine the prevalence of CHF and associated risk factors in a multiethnic community, a population sample of 2759 elderly (i.e., 65 years of age and older) African American (AA), Hispanic-Cuban (HC), and white non-Hispanic (WNH) men and women from Miami-Dade County, Florida, were examined. There were 153 (5.6%) cases of self-reported CHF in the sample. The unadjusted prevalence rate of CHF was virtually identical among elderly AA (4.8%) and WNH (4.9%) but was significantly (p=0.04) lower than the rate among HC (6.8%). Sex- and ethnic-specific analyses showed that the highest prevalence rate of CHF was among HC women (8.2%). A multiple logistic analysis was used to calculate the odds ratio (OR) and 95% confidence interval (CI) of CHF in relation to age, sex, ethnicity, medical history, and smoking and alcohol drinking habits. Age (65-74 vs. 75-84; OR 1.7; CI 1.2-2.4; p=0.01), HC ethnic group (OR 1.5; CI 1.0-2.4; p=0.05), history of hypertension (OR 1.5; CI 1.1-2.1; p=0.02), history of myocardial infarction (OR 2.3; CI 1.5-3.5; p=0.0001), and history of diabetes mellitus (OR 1.9; CI 1.3-2.8; p=0.001) were directly, significantly, and independently associated with the prevalence of self-reported CHF. The findings here confirm those of prior studies in elderly white US residents, which indicate that heart attack, hypertension, and diabetes mellitus are major risk factors for CHF. The results also show that elderly AA and WNH have similar CHF prevalence rates. The higher CHF prevalence in elderly HC women found in this study requires further investigation. (c)2001 by CHF, Inc.     

Isomerism of the atrial appendages associated with 22q11 deletion in a fetus.

There is a strong association between prenatally diagnosed structural heart disease and fetal chromosomal abnormalities. Isomerism of the atrial appendages is an exception to this because the fetal karyotype is usually normal in this condition. A case of atrial isomerism diagnosed antenatally with a normal female karyotype but with a microdeletion of chromosome 22q11 is reported.     

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5- to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for “diseases of cortical connectivity” thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbumin-labeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism.