Kenneth J. Dooley

Population-based study of congenital heart defects in Down syndrome.

Mental retardation and hypotonia are found in virtually all Down syndrome (DS) individuals, whereas congenital heart defects (CHDs) are only present in a subset of cases. Although there have been numerous reports of the frequency of CHDs in DS, few of the studies have had complete ascertainment of DS in a defined geographic area. The Atlanta Down Syndrome Project, a population-based study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth prevalence: 9.6/10,000). Cardiac diagnoses were available on 227 (93%) of the cases and 89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44% had CHDs including 45% atrioventricular septal defect (with or without other CHDs), 35% ventricular septal defect (with or without other CHDs), 8% isolated secundum atrial septal defect, 7%, isolated persistent patent ductus arteriosus, 4% isolated tetralogy of Fallot, and 1% other. This report is unique in that it contains the largest number of trisomy 21 infants ascertained in a population-based study where modern techniques for diagnosing cardiac abnormalities predominate.

Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project

Purpose: The population-based National Down Syndrome Project combined epidemiological and molecular methods to study congenital heart defects in Down syndrome.Methods: Between 2000 and 2004, six sites collected DNA, clinical, and epidemiological information on parents and infants. We used logistic regression to examine factors associated with the most common Down syndrome-associated heart defects.Results: Of 1469 eligible infants, major cardiac defects were present in 44%; atrioventricular septal defect (39%), secundum atrial septal defect (42%), ventricular septal defect (43%), and tetralogy of Fallot (6%). Atrioventricular septal defects showed the most significant sex and ethnic differences with twice as many affected females (odds ratio, 1.93; 95% confidence interval, 1.40–2.67) and, compared with whites, twice as many blacks (odds ratio, 2.06; 95% confidence interval, 1.32–3.21) and half as many Hispanics (odds ratio, 0.48; 95% confidence interval, 0.30–0.77). No associations were found with origin of the nondisjunction error or with the presence of gastrointestinal defects.Conclusions: Sex and ethnic differences exist for atrioventricular septal defects in Down syndrome. Identification of genetic and environmental risk factors associated with these differences is essential to our understanding of the etiology of congenital heart defects.

Risk factors for conotruncal cardiac defects in Atlanta

Because the causes of conotruncal cardiac defects are poorly understood, a case-control study was conducted to investigate maternal risk factors for conotruncal cardiac defects. Eligible cases included all infants who were born from 1976 through 1980 to residents of the five county metropolitan Atlanta area and diagnosed with truncus arteriosus, transposition of the great arteries or tetralogy of Fallot. Eligible control infants were a sample of comparable infants without birth defects. Maternal interviews were conducted for 73% (83 of 114) of eligible cases and 72% (1,303 of 1,804) of eligible control infants. The results showed increased risks associated with maternal diabetes (odds ratio 5.6; 90% confidence interval 2.5 to 15.6), maternal stress related to job loss, divorce, separation or death of a close friend or relative (odds ratio 2.4; 90% confidence interval 1.4 to 4.2) and a history of a sibling with a cardiac defect (odds ratio 4.8; 90% confidence interval 2.2 to 10.5). The statistical power of the data was adequate to rule out threefold or greater increases in risk for a wide variety of other exposures, including maternal illnesses other than diabetes, contraceptive use, nonmedicinal drugs (for example, coffee, tea, alcohol, cigarettes, street drugs), employment and education. This population-based study offers no clues that could explain either the high rate of transposition of the great arteries or the temporal trend of an increasing rate of tetralogy of Fallot in Atlanta.

Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome

Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS‐associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10‐methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine β‐synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele‐sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r2≥0.8) with the nonsynonymous coding SNP rs1051266 (c.80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was over‐transmitted to cases with AVSD (P=0.05) and under‐transmitted to controls (P=0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS. Genet. Epidemiol. 34: 603–612, 2010.

An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects

About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ∼65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.

CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in down syndrome

Cheryl L. Maslen,* Darcie Babcock, Susan W. Robinson, Lora J.H. Bean, Kenneth J. Dooley, Virginia L. Willour, and Stephanie L. Sherman Department of Medicine, Division of Endocrinology, Oregon Health & Science University, Portland, Oregon Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon Heart Research Center, Oregon Health & Science University, Portland, Oregon Department of Human Genetics, Emory University, Atlanta, Georgia Department of Pediatrics, Sibley Heart Center, Cardiology, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland

Follow-up of surgical correction of vascular anomalies causing tracheobronchial compression

SummaryBetween January 1977 and January 1990, 44 patients with symptomatic vascular rings/slings required surgical intervention at this center. Nineteen patients had double aortic arch (group I); 13 patients had vascular ring consisting of right aortic arch, anomalous origin of the left subclavian artery, and ligamentum arteriosus (group II); eight patients had innominate artery compression (group III); and four patients had pulmonary artery sling (group IV). Three patients had complex congenital heart defect and died secondary to it and are excluded from the study. Follow-up was obtained on 31 patients (76%). The follow-up period ranged from 0.4 years to 10.9 years, with a mean of 3.6 years. Seventy percent of the overall group were asymptomatic, and 30% of patients continued to have upper and lower respiratory symptoms on late follow-up. One third of patients in groups I and II, who underwent surgical repair, continue to have symptoms. Patients who have persistent symptoms should be further evaluated with PFTs, MRI, and bronchoscopy, and may benefit from aortopexy. Patients with innominate artery compression and pulmonary artery sling do well soon after surgery with relief of most of their symptoms.

Effects of venovenous extracorporeal membrane oxygenation on cardiac performance as determined by echocardiographic measurements.

We evaluated the effects of venovenous extracorporeal membrane oxygenation (ECMO) on cardiac performance by echocardiographic measurements in 15 infants. Heart rate and blood pressure were also recorded. Echocardiographic measurements included aortic and pulmonary peak blood flow velocities, pulmonary time to peak velocity, left ventricular shortening fraction, velocity of circumferential fiber shortening corrected for heart rate, and peak systolic wall stress before, during, and after venovenous ECMO. Pre-ECMO echocardiograms showed borderline or normal indexes of cardiac function. After initiation of venovenous ECMO, all infants had normalization and no infant had deterioration of cardiac performance. The inotropic agents dopamine and dobutamine were decreased from average doses of 12 and 3.6 micrograms/kg per minute, respectively, to 3.7 and 1.3 micrograms/kg per minute, respectively, within 8.8 hours of the institution of venovenous ECMO. During this time the mean arterial pressure remained stable, and the heart rate decreased (169 +/- 21 vs 136 +/- 15 beats/min; p < 0.001). During the course of ECMO there were no changes in left ventricular shortening fraction, velocity of circumferential fiber shortening corrected for heart rate, or aortic peak blood flow velocities. Pulmonary artery peak blood flow velocity (69 +/- 22 vs 92 +/- 28 cm/sec; p = 0.04) and pulmonary time to peak velocity improved (47 +/- 11 vs 65 +/- 16 msec; p = 0.026). We conclude that venovenous ECMO does not have deleterious effects on cardiac performance.

Range-gated pulsed Doppler ultrasonographic evaluation of carotid arterial blood flow in small preterm infants with patent ductus arteriosus

Range-gated pulsed Doppler (RGPD) ultrasonography was utilized to study the effect of a patent ductus arteriosus (PDA) on carotid arterial blood flow in small preterm infants. Carotid arterial flow velocity studies were performed on 23 preterm infants, sampling right and left carotid arteries. Studies on seven infants after PDA ligation and on seven who developed no evidence of PDA were used as controls. A strong relationship was demonstrated between diastolic reversal in the carotid arteries and PDA. The results of this study indicate that the RGPD flow velocity curve from the carotid artery is more sensitive than M-mode echocardiography or clinical examination in detecting PDA, and that PDA in small preterm infants is associated with a distinct abnormality in the carotid arterial flow pattern.

Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project

BACKGROUND Maternal folic acid supplementation has been associated with a reduced risk for neural tube defects and may be associated with a reduced risk for congenital heart defects and other birth defects. Individuals with Down syndrome are at high risk for congenital heart defects and have been shown to have abnormal folate metabolism. METHODS As part of the population-based case-control National Down Syndrome Project, 1011 mothers of infants with Down syndrome reported their use of supplements containing folic acid. These data were used to determine whether a lack of periconceptional maternal folic acid supplementation is associated with congenital heart defects in Down syndrome. We used logistic regression to test the relationship between maternal folic acid supplementation and the frequency of specific heart defects correcting for maternal race or ethnicity, proband sex, maternal use of alcohol and cigarettes, and maternal age at conception. RESULTS Lack of maternal folic acid supplementation was more frequent among infants with Down syndrome and atrioventricular septal defects (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.08-2.63; p = 0.011) or atrial septal defects (OR, 1.69; 95% CI, 1.11-2.58; p = 0.007) than among infants with Down syndrome and no heart defect. Preliminary evidence suggests that the patterns of association differ by race or ethnicity and sex of the proband. There was no statistically significant association with ventricular septal defects (OR, 1.26; 95% CI, 0.85-1.87; p = 0.124). CONCLUSIONS Our results suggest that lack of maternal folic acid supplementation is associated with septal defects in infants with Down syndrome. Birth Defects Research (Part A), 2011.