Publications

Folate deficiency is associated with an increased risk of conotruncal heart defects (CTHD), but interactions with genetic factors remain unclear. Our objective was to investigate genome-wide associations between genetic variants and birth before versus after universal folic acid fortification among children with CTHD and other heart defects. Genetic sequencing data were available through the Pediatric Cardiac Genomics Consortium. Sequencing data were aligned to the human reference genome (GRCh38/hg38) and jointly processed to ensure uniform variant detection and minimize batch effects. Analyses were restricted to individuals with European-inferred genetic ancestry. GWAS models were implemented to explore the association of common variants with fortification eras among all participants (n=1285), the subset of individuals with CTHD (n=534), and the remaining individuals with other heart defects (n=751). Functional enrichment was assessed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Among the full analytic group, eight loci had at least two nominally-enriched variants before compared to after fortification. Among the subset with CTHD, two variants located in DHRS3 (rs7551703, OR 2.10, and rs6541043, OR 2.21) and four variants located in PPARGC1β were nominally enriched after fortification (OR 4.47-4.51). Enriched biological pathway terms were consistent with cardiac developmental processes. In summary, this study examined the association between folic acid fortification and genetic risk for CTHD and other heart defects and identified associations with fortification era that may suggest some shift in risk following fortification. Identified pathways suggest gene-nutrient interactions may modulate cardiac developmental pathways, underscoring the relationship between maternal folate status and cardiovascular development.

BACKGROUND: Children with congenital heart disease (CHD) experience neurodevelopmental challenges, arising in part from altered brain maturation beginning in utero. There are currently no prenatal interventions to mitigate this risk. Foetal CHD is associated with alterations in maternal blood pressure (BP), for which therapies are available, so we investigated associations between maternal BP, foetal cerebral haemodynamics, and brain growth in foetuses with and without CHD.

METHODS: Our single-centre retrospective cohort study first analysed maternal BP during pregnancy stratified by foetal CHD (n = 494), other foetal anomalies (n = 769), or no foetal anomalies (n = 111). We then performed a prospective study linking maternal BP with foetal brain MRI and cerebral and umbilical Doppler measures in pregnancies with foetal CHD (n = 97 MRI; 121 Doppler) and those with no foetal anomalies (n = 111 MRI; 86 Doppler).

FINDINGS: Mothers carrying a foetus with CHD showed a distinct BP profile compared with unaffected controls and non-CHD foetal anomaly pregnancies. In CHD pregnancies, but not in controls, lower maternal diastolic BP was associated with lower cerebrovascular resistance, lower cerebroplacental flow ratio, and an attenuated reduction in foetal cortical surface area in sensorimotor, frontal and temporal cortical regions.

INTERPRETATION: Lower maternal diastolic BP may reflect adaptive maternal-foetal circulatory coupling that enhances foetal cerebral perfusion and mitigates cortical growth impairment in CHD. We observe a link between maternal haemodynamics and foetal brain maturation in CHD, warranting further exploration in interventional studies.

FUNDING: Supported by the NINDS (R01NS114087, K23NS101120), NIBIB (R01EB031170), NHLBI (K08HL157653), AAN Clinical Research Training Fellowship, BBRF Young Investigator Awards, and the Farb Family Fund.

OBJECTIVE: To evaluate risk factors for mortality and discharge timing in preterm infants born before 35 weeks' gestational age (GA) with congenital heart disease (CHD).

STUDY DESIGN: Retrospective cohort study using Children's Hospitals Neonatal Consortium data from 2010-2024. Infants <35 weeks' GA with CHD were included. Primary and secondary outcomes were in-hospital mortality and post-menstrual age (PMA) at discharge. CHD subtypes were categorized as compromised systemic output, sustained cyanosis, or congestive heart failure. Multivariable generalized linear mixed models were used.

RESULTS: Among 11,261 preterm infants with CHD, mortality was 13.7%. Significant interactions between CHD subtype and gestational age were observed. Among infants with congestive heart failure, those 30-32 weeks' GA had higher mortality compared with <27 weeks' GA (adjusted odds ratio [aOR] 1.46, 95% confidence interval [CI], 1.06-2.02, p=0.012), and those 27-29 weeks GA had lower mortality odds compared with 30-32 weeks (aOR 0.69, 95% CI, 0.52-0.90, p=0.002). Surgical necrotizing enterocolitis, delivery room intubation, and trisomy 21 were the strongest mortality predictors (aOR 3.12, 2.69 and 2.27, respectively; all p<0.001). Higher GA was associated with earlier PMA at discharge (-2.4 weeks for 30-32 weeks GA vs <27 weeks GA; p<0.001).

CONCLUSIONS: Short-term outcomes vary by CHD subtype and comorbidities. Older GA was unrelated to inpatient mortality. Potentially modifiable factors such as necrotizing enterocolitis and infections could inform care. Future work incorporating prenatal decisions and surgical timing is needed.

OBJECTIVE: Concurrent development of the placenta and heart during early gestation suggests a shared biological basis for the co-occurrence of abnormal placentation and congenital heart disease (CHD). This study investigated the association between placental vascular pathology and CHD type.

METHODS: A retrospective study at two institutions included CHD (n = 521) and unaffected (n = 122) infants. CHDs were categorized into three groups (left and right ventricular outflow tract obstruction and mixed lesions) based on the anticipated effect of placental venous return streaming toward the fetal brain. Placental pathological findings were categorized by the Amsterdam criteria. The rate of placental pathology was compared between cases and controls and across the three CHD groups.

RESULTS: CHD had higher rates of maternal vascular malperfusion (MVM) (0.31 vs. 0.05, p < 0.001). Comparison within CHD groups demonstrated similar rates of MVM, while fetal vascular malperfusion (FVM) was significantly higher in groups with reduced fetal cerebral oxygenation (p = 0.037). MVM was associated with low birth weight (OR = 0.28, p < 0.001), and FVM was associated with increased maternal age (OR = 1.07, p = 0.037). No significant associations were identified in other placental pathologies.

CONCLUSION: This study offers valuable insights into the connection between placental dysfunction and CHD, identifying that MVM is significantly associated with CHD development.

BACKGROUND: Neonatal disorders such as post-infectious hydrocephalus exhibit a higher incidence in Africa, where the intricate relationships between genetic ancestry, environmental exposures, and other risk factors likely contribute to the increased incidence.

METHODS: To start to characterize the common genetic architecture of Ugandan infants, we analyzed genome sequencing data from 1,030 Ugandan infants recruited from studies targeting neonatal sepsis and hydrocephalus. We employed genetic admixture analysis and integrated geospatial data to examine the relationships between genetic backgrounds and disease prevalence within this cohort.

RESULTS: Our results identified four distinct genetic admixture groups, each correlating strongly with specific geographic distributions across Uganda. Notably, a predominance of one admixture group, most common in northern Uganda, was overrepresented in the participants with post-infectious hydrocephalus.

CONCLUSION: This study underscores the importance of genetic factors in disease manifestation at the population level, and a role for such precision public health approaches in complex neonatal disorders in African populations.

Predicting the functional significance of structural variants (SVs) associated with genetic diseases remains challenging. To test the hypothesis that SVs from people with congenital heart disease (CHD) disrupt developmental chromatin interactions, we developed CardioAkita, a machine-learning model that predicts how variants alter 3D chromatin structure. Analyzing previously genotyped de novo SVs ( dn SVs), we observed a positive association between CHD severity and CardioAkita scores across dozens of families. From whole-genome sequencing of three individuals with CHD we predicted disruptive dn SVs. Induced pluripotent stem cells engineered to harbor these variants confirmed CardioAkita's predictions of 3D chromatin changes, and further revealed aberrant expression of local genes including cardiac developmental genes, suggesting that chromatin reorganization plays a significant mechanistic role in the genetic etiology of CHD. Our findings highlight the potential for models of 3D chromatin organization to predict the pathogenicity and underlying mechanisms of SVs in human disease.

OBJECTIVE: Investigate the association between placental vascular abnormalities and regional brain volumes in congenital heart disease (CHD) fetuses with and without genetic abnormalities.

STUDY DESIGN: Secondary analysis of brain magnetic resonance imaging (MRI) and placental pathology data from 121 CHD fetuses enrolled in prospective neuroimaging studies at two centers.

RESULTS: Placental vascular abnormality was present in 46% of fetuses, and genetic abnormality was present in 19%, including 12% with both abnormalities. Fetuses with the combination of placental and genetic abnormalities had smaller brain volumes compared to fetuses without either abnormality for total brain, subcortical gray matter, brainstem, and cerebellum, with a significant interaction (P < 0.05) between placental and genetic abnormalities for intracranial and subcortical gray matter volumes.

CONCLUSION: Smaller brain volumes for CHD fetuses with placental and genetic abnormalities may suggest common genetic pathways affect placental, heart, and brain development, or that genetic abnormalities heighten vulnerability when placental changes occur.

BACKGROUND: Thrombotic events, including acute ischemic stroke, are more common in individuals with congenital heart disease (CHD). Whether common thrombophilia variants contribute to thrombotic risk in this population remains unclear. We evaluated whether prothrombin G20210A (F2 c.97G>A) and factor V Leiden (F5 c.1601G>A; p.Arg534Gln) are associated with thrombotic events in CHD.

METHODS: Participants in the Pediatric Cardiac Genomics Consortium with exome sequencing and electronic medical record data were identified. Individuals were stratified by prothrombin G20210A and factor V Leiden genotypes, ventricular physiology, and antithrombotic therapy. The primary outcome was the presence of International Classification of Diseases (ICD) or Phecodes (phenotype codes) for thrombotic events.

RESULTS: Among 4008 participants (median age, 11.4 [interquartile range, 5.1-17.9] years; 44.4% boys), thrombotic events occurred in 737 (18%), including 93 (13%) with acute ischemic stroke. Compared with the Genome Aggregation Database, the CHD cohort had a lower prevalence of heterozygous prothrombin G20210A and factor V Leiden variants. Variant prevalence did not differ between participants with and without thrombotic events. Single-ventricle CHD was associated with higher thrombosis frequency than biventricular CHD (35% versus 16%, P≤0.0001), without differences in variant prevalence.

CONCLUSIONS: In this multicenter CHD cohort, prothrombin G20210A and factor V Leiden were not significantly associated with thrombotic outcomes, supporting recommendations against routine screening. Given low variant prevalence, the study was powered to exclude only large associations. Reduced variant frequency suggests survivorship bias beginning in fetal life. Larger integrated clinical-genomic studies are needed to refine thrombotic risk stratification in CHD.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03347214.