Our Research

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.