About

Elizabeth Goldmuntz, MD, MSHP, FAAP, FACC, is a Professor of Pediatrics (Cardiology) at the Children's Hospital of Philadelphia. She serves as a Consultant at Pennsylvania Hospital and is an Attending Physician at the Fetal Heart Center, Children's Hospital of Philadelphia. She also holds the position of Associate Chief Clinical Research Officer at the Children's Hospital of Philadelphia Research Institute. Her educational background includes a B.A. in History from Yale University, an M.D. from the University of Pennsylvania School of Medicine, and an M.S. in Health Policy Research from the University of Pennsylvania Perelman School of Medicine. Her research and clinical interests focus on pediatric cardiology, with particular emphasis on fetal heart conditions and congenital heart disease.

Research topics

• Internal medicine
• Biology
• Genetics
• Medicine
• Computational biology
• Bioinformatics

Selected publications

• Machine learning to infer neurocognitive testing scores among adolescents and young adults with congenital heart disease

  Communications Medicine · 2026-02-06 · 1 citations

  articleOpen access

  Congenital heart disease (CHD) affects about 1% of births and is linked to differences in thinking and learning. Understanding how birth, genetic, clinical, and environmental factors together explain cognitive variability can inform monitoring and care. This study builds a multivariate model predicting cognition across multiple domains in adolescents and young adults with CHD. We studied 89 adolescents and young adults (AYAs; mean age 16 years) with CHD who completed structural and diffusion MRI and fifteen neurocognitive tests across seven domains. Using an enhanced forward-inclusion and backward-elimination strategy with cross-validation, we built multivariate models incorporating biological, socioeconomic, clinical, genetic, and brain imaging features. Performance was evaluated using Pearson correlation ($$r$$) between observed and inferred scores, mean absolute error (MAE), and inverse inferability score (IIS). Here we show that models infer scores with moderate accuracy ($$r$$ = 0.245–0.648; MAE = 1.6–12.0 points; mean MAE = 6.3). Highest correlations include Digit Span ($$r$$ = 0.65; p < 0.001), Verbal Comprehension Index ($$r$$ = 0.594; p < 0.001), and Matrix Reasoning ($$r$$ = 0.574; p < 0.001). Domain ranking by IIS shows the best (lowest) scores for general intelligence (0.0886), followed by working memory (0.7100), and a higher (worse) score for perceptual reasoning (1.9199). A multivariate approach combining brain imaging with genetic, clinical, and environmental factors provides clinically meaningful inference of individual cognitive performance in AYAs with CHD. These findings suggest complementary roles of brain, genetic, and contextual factors in shaping cognitive variability and motivate validation in larger cohorts. Children born with congenital heart disease can have differences in thinking and learning. We aimed to learn which factors, brain structure, genetics, medical history, and family environment, explain these differences in teens and young adults. We combined brain scans with health, family, and genetic information and used computer models to estimate scores on standard tests. The models reasonably estimated individual scores; some abilities, such as general thinking skills, working memory, and processing speed, were estimated more accurately than others. These findings suggest that brain scans, together with medical and family information, can provide a clearer picture of thinking skills. With further testing in larger, diverse groups, this approach could help guide follow‑up care tailored to each person. Hussain et al. build multivariate machine-learning models integrating brain MRI with genetic, clinical and socioeconomic data to infer 15 neurocognitive test scores in adolescents and young adults with congenital heart disease. The models achieve moderate accuracy and highlight joint brain, genetic, and contextual contributions.

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• P204: Evaluating the clinical validity of gene-disease relationships in congenital heart disease

  Genetics in Medicine Open · 2026-01-01

  articleOpen access

  referrals), long-term management (eg, clinical guidelines, lifestyle recommendations, care goals), and prognosis were documented, and cardiac, extra-cardiac, neurodevelopmental, and growth outcomes were assessed at 6 months and 4 years post-genetic testing consult.Clinical management changes and health outcomes were compared across demographics, lesion types, and genetic testing results using a Chi-Squared, Fisher's, or Welch's test (p<0.05).Results: Analysis of 120 patient charts showed a CHD-specific diagnostic yield of 23.9% from genetic testing, with an additional 8.3% of patients receiving an incidental diagnosis unrelated to the CHD lesion.The frequency of diagnostic results did not differ between cardiac lesion types (p=0.159).Genetic testing results led to a significant management change in 27.5% of all patients, driven primarily by those with a CHD-specific diagnostic result, 79.3% of whom had a management change.Short-term management changes occurred more frequently than long-term changes, affecting 75.9% and 65.5% of patients with a diagnostic genetic test, but their frequency did not significantly differ across CHD lesion types (p=0.171 and p=0.0614, respectively).In patients with a diagnostic test, referrals to outside specialties were the most common management change (62.1%).Seventy-five point eight percent of diagnosed patients experienced a change in prognosis, most often affecting neurodevelopmental prognosis (58.6%).At 6 months patients with a diagnostic genetic test had a higher frequency of adverse cardiac outcomes than those with a non-diagnostic test (p=0.028);however, this difference had resolved by 4 years (p>0.999),possibly due to survivor bias given decreased survival in the diagnostic group (p=0.009).Those with a diagnostic test also had delayed neurodevelopment (p=0.044) at 4 years.Conclusion: Genetic testing in infants with CHD significantly influenced clinical management, with diagnostic results driving both short-and long-term changes in care and impacting prognoses.The association between adverse outcomes and diagnostic findings likely reflects the increased risk of complex multisystem disease in many genetic syndromes rather than the testing itself.As all recommended patients underwent genetic testing, comparisons with untested patients could not be performed.Additionally, this analysis includes only the first 120 eligible patients, and ongoing work will evaluate the remaining cohort and expand these findings.Importantly, genetic testing continues to demonstrate clear benefits in guiding individualized care, multidisciplinary planning, and anticipatory guidance relating to both the cardiac lesion and extra-cardiac manifestations.These findings can help standardize genetic screening at Children's Wisconsin and inform care across the broader CHD population.Future work should include prospective studies to evaluate long-term impacts of genetic testing and ethical considerations of genome and exome sequencing in this young patient population.

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• A novel spliceosomopathy caused by de novo SF3B3 variants

  Genome Medicine · 2026-02-19 · 1 citations

  articleOpen access

  Abstract Background Spliceosomopathies are syndromes caused by pathogenic variants in genes involved in splicing and mRNA metabolism. Here, we report a novel spliceosomopathy caused by de novo variants in SF3B3, encoding a subunit of the spliceosomal SF3b complex. Methods We performed genomic, clinical, computer-aided gestalt analysis, molecular dynamics simulations, and functional studies using patient-derived fibroblasts. Results Through international data sharing, we collected clinical and molecular data from 24 unrelated individuals with heterozygous SF3B3 variants, mostly missense, consistent with autosomal dominant inheritance. Individuals exhibited a congruent phenotype including autism spectrum disorder (ASD), developmental delay (DD), intellectual disability (ID), language and motor delay, multiple congenital anomalies, and distinctive craniofacial features, confirmed by GestaltMatcher analysis. In patient fibroblasts, SF3B3 mRNA was within the normal range, whereas protein levels were reduced by approximately 15–30% depending on the variant. All-atom simulations revealed impaired interactions of mutant SF3B3 with SF3b components. Transcriptome profiling revealed widespread gene expression changes, including genes involved in cell-cycle regulation, urogenital development, heart morphogenesis, neural crest differentiation, and neurogenesis. Alternative splicing analyses demonstrated specific alterations, including increased retained intron events. Functional assays confirmed cell-cycle abnormalities in patient-derived fibroblasts. Conclusions SF3B3 variants cause a novel spliceosomopathy with a continuous clinical spectrum, from extremely severe prenatal forms with perinatal lethality to a milder form with autism ASD and DD/ID. These variants alter both stability and function of the SF3b complex, resulting in dysregulated transcriptome, alternative splicing defects, and downstream cellular consequences such as cell-cycle perturbation.

  PublisherDOI

• <i>ROBO2</i> Variants Associated With Atrial Septal Defect Define a Novel Regulatory Element

  Circulation Genomic and Precision Medicine · 2026-02-16

  articleOpen access

  BACKGROUND: Atrial septal defects (ASDs) are a prevalent type of congenital heart disease. Previous GWAS (Genome-Wide Association Studies) have identified common variants associated with ASDs, though their mechanisms remain unknown. We aimed to expand insights into the architecture of common variants associated with ASD risk and elucidate functional mechanisms. METHODS: We conducted a GWAS using isolated ASD cases and healthy controls and replicated findings in an independent cohort. We examined epigenetic marks within this ASD locus in human induced pluripotent stem cell-derived cardiomyocytes and fetal human hearts. We characterized the consequences of deletions introduced by CRISPR-Cas9 mutagenesis of human induced pluripotent stem cells to assess the effect on downstream gene expression. In addition, we investigated the 3-dimensional genome architecture of the locus using chromosome conformation capture sequencing. RESULTS: We identified a novel ASD locus on chromosome 3p12.3 encompassing the ROBO2 gene, which encodes the Roundabout guidance receptor 2 for Slit ligands. This locus includes 15 common single nucleotide polymorphisms, an enhancer, and a CCCTC-binding factor (CTCF)-binding site. Deletions of varying lengths within the ASD-associated locus in human induced pluripotent stem cell-derived cardiomyocytes reduced ROBO2 expression and dysregulated the expression of extracellular matrix genes. Chromosome conformation capture sequencing indicated that this region physically interacts with the ROBO2 promoter and demonstrates that the CTCF-binding site is essential for this contact. CONCLUSIONS: Novel common single nucleotide polymorphisms in regulatory elements controlling ROBO2 transcription contribute to risk for ASDs. These data infer key roles for the Roundabout guidance receptor 2 and Slit ligands in embryogenic development and maturation of the atrial septa.

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• Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion

  Molecular Psychiatry · 2026-04-15

  articleOpen access

  Schizophrenia develops in one in every four individuals with a pathogenic 22q11.2 deletion, yet the genetic modifiers influencing the manifestation of schizophrenia in this high-risk group remain incompletely understood. Here, we identify rare tandem repeat expansions (TREs) as significant contributors to schizophrenia risk in this population. Genome sequencing of 438 unrelated individuals with 22q11.2 deletions revealed a marked enrichment of rare genic TREs among those with schizophrenia, with effect sizes comparable to common polygenic risk. These TREs are disproportionately located in intronic and splice-adjacent regions relative to other genomic regions, with evidence suggesting that they disrupt gene regulation through mechanisms including altered methylation and splicing. Cell-type-specific analyses indicate that TREs are primarily associated with differentially expressed genes in excitatory and inhibitory neurons in the prefrontal cortex. Affected genes, including DLGAP2 and DMPK, are involved in neurodevelopment and synaptic organization. These findings extend the role of TREs as genetic modifiers, providing new insights into the molecular mechanisms underlying schizophrenia in this ultra-high-risk population and into the broader biology of idiopathic schizophrenia.

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• Prevalence and Spectrum of Congenital Heart Disease in Individuals With Distal Chromosome 22q11.22–23 Deletions

  Clinical Genetics · 2025-12-08

  articleOpen access

  This study is aimed at determining the spectrum of congenital heart disease associated with distal 22q11.22-23 deletions flanked by low copy repeats, LCR22 D-H. We analyzed cardiology findings in 128 unrelated individuals with distal LCR22 D-H deletions. A total of 62 were newly described and 66 were derived from previous reports. We found that deletions which included LCR22-D as the proximal endpoint were the most prevalent in the cohort (104/128, 81.3%). Clinically relevant congenital heart disease was identified in 48 individuals (37.5%, 95% CI 29%-46%), which is lower than the prevalence reported for typical, proximal LCR22 A-D deletions (p = 3.7E-4), especially for conotruncal defects (13/128, 10.2%; p = 7.1E-13). Mild to moderate CHD predominated, including ventricular septal defects (22/128), bicuspid aortic valve (9/128) and mild cardiomyopathy (3/128). Persistent truncus arteriosus was the most prevalent (n = 8/13) conotruncal heart defect, but other anomalies also occurred in singleton cases. These findings support the need for cardiac evaluation in all individuals with distal 22q11.22-23 deletions, increased use of clinical genetic testing in syndromic individuals with these findings, and molecular studies in model systems. The results demonstrate that reduced gene dosage of distal 22q11.21-23, particularly within the D-E region including MAPK1 and HIC2 convey risk for CHD.

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• Clinical Outcome Prediction Model in Tetralogy of Fallot Without Pulmonary Valve Replacement Using Contraction Fraction From the SCOUT‐TOF Registry

  Journal of the American Heart Association · 2025-05-13 · 3 citations

  articleOpen access

  Background Few large scale prediction models of clinical outcomes in repaired tetralogy of Fallot (rTOF) exist. Further, contraction fraction, a novel parameter indexing stroke volume by mass reflecting myocardial efficiency, has not been studied. The goals of this study were to develop and validate an rTOF prediction model of clinical outcome from a single center, the SCOUT‐TOF (Single Center Outcomes Using Cardiac Magnetic Resonance in Tetralogy of Fallot) registry, using readily available cardiac magnetic resonance parameters and explore novel metrics. Methods and Results We retrospectively reviewed cardiac magnetic resonance parameters of patients with rTOF undergoing cardiac magnetic resonance from 2005 to 2021. Composite outcome 1 (CO1) included death, transplantation, ventricular tachycardia, and pacemaker placement, and composite outcome 2 (CO2) added cardiovascular hospitalizations. An elastic net was used to identify significant variables to enter a best subsets logistic regression. A group of 761 patients with rTOF were studied with a median follow‐up of 4.15 years; 31 and 44 CO1 and CO2 events occurred respectively. Right ventricular (RV) contraction fraction was the most significant predictor for CO1 (area under the curve, 0.72; odds ratio [OR], 0.54; P =0.01) and CO2 (area under the curve, 0.69; OR, 0.60; P =0.01). RV contraction fraction was lower for those met that CO1 and CO2 end points (median 1.84 [1.48–2.39] versus 2.34 [1.72–3.02] and 1.88 [1.51–2.53] versus 2.34 [1.72–3.02] cc×cm 2.7 /g×m 1.4 , P &lt;0.01 respectively). Additional significant predictors for CO1 were indexed RV mass/volume and left ventricular ejection fraction whereas for CO2, left ventricular global function index and left ventricular mass were additional predictors. Conclusions In rTOF, RV contraction fraction, a novel biomarker of ventricular efficiency, may be used to possibly improve risk stratification. In addition, not only RV but left ventricular measures of remodeling should be considered in the follow‐up of these patients.

  PublisherDOI

• Abstract 4367228: Asymmetric Pulmonary Artery Geometry Drives Branch-Specific Shear Stress Patterns in Repaired Tetralogy of Fallot: A Substudy of the <i>Single Center Cardiac Magnetic Resonance Outcomes Registry – Tetralogy of Fallot</i>

  Circulation · 2025-11-03

  article

  Introduction: In repaired tetralogy of Fallot (rToF), asymmetric remodeling of the pulmonary arteries (PA) leads to branch-specific hemodynamic changes. Geometric factors such as curvature influence wall shear stress (WSS) patterns, with distinct effects between the left (LPA) and right pulmonary arteries (RPA). Oscillatory shear index (OSI), which quantifies directional changes in WSS over the cardiac cycle, is a key marker of disturbed flow. This study investigates how curvature and other geometric factors influence hemodynamics in these two branches. Hypothesis: We hypothesize that geometric features influence PA hemodynamics in a branch-specific manner, with curvature having a stronger association with shear-related metrics in certain regions compared to others. Methods: Patient-specific PA models (n = 22) were reconstructed from cardiac magnetic resonance imaging, and computational fluid dynamics simulations were performed under steady and pulsatile flow conditions with patient-derived boundary conditions. Geometric parameters, including curvature and tortuosity, and hemodynamic metrics, including time-averaged WSS and OSI, were quantified. Spearman correlations assessed branch-specific relationships. Results: In the LPA, curvature showed a strong positive correlation with time-averaged WSS (ρ = 0.56, p = 0.006) and a negative correlation with OSI (ρ = -0.52, p = 0.013), indicating that higher curvature segments exhibit more unidirectional, high-shear flow (Figures 1 and 2) . In contrast, RPA curvature did not correlate significantly with any of the measured hemodynamic variables (all p &gt; 0.28). The LPA curvature was significantly greater than the RPA curvature (p = 0.015). Tortuosity did not show significant correlations with hemodynamics in either branch (p &gt; 0.17), suggesting that curvature is the dominant geometric modulator of wall shear stress (Table 1) . Conclusions: The LPA’s curvature-dependent hemodynamics characterized by significant time-averaged WSS and OSI patterns contrast with the RPA’s lack of such correlations. Anatomically, the RPA’s straighter anatomy minimizes flow disruption whereas the LPA curvature increases flow disruption. This study’s results align with prior studies showing sharper angulation in the LPA post-repair, promoting flow acceleration. Clinically, these findings highlight the importance of branch-specific geometric and hemodynamic assessments in rToF follow-up.

  PublisherDOI

• Machine Learning to Infer Neurocognitive Testing Scores Among Adolescents and Young Adults with Congenital Heart Disease

  Research Square · 2025-06-06

  preprintOpen access
  PublisherOA PDFDOI

• Pulmonary Artery Shear Stress and Oscillatory Shear Index are Associated with Right Ventricular Remodeling in Repaired Tetralogy of Fallot

  Annals of Biomedical Engineering · 2025-07-03 · 2 citations

  articleOpen access

  Abstract Purpose Right ventricular (RV) remodeling in repaired tetralogy of Fallot (rToF) is a multifactorial process that may be affected by downstream hemodynamics. We therefore sought to characterize hemodynamics in the pulmonary arteries (PAs) of rToF patients using cardiovascular magnetic resonance (CMR)-derived computational fluid dynamics (CFD) and to study these variables in association with RV measurements at follow-up. Methods We selected patients with two CMRs who had magnetic resonance angiography (MRA) performed at baseline. The PA was segmented from the main PA (MPA) through the first bifurcation of the left PA (LPA) and right PA (RPA). Both steady and pulsatile simulations were performed. For each vessel, we calculated curvature, tortuosity, and both average (avg) and peak steady WSS (WSS steady ), time-averaged WSS (taWSS), WSS in systole (WSS systole ), and WSS in diastole (WSS diastole ), as well as oscillatory shear index (OSI). We studied these variables in association with RV metrics at follow-up including: RV end-diastolic volume index (RVEDVi), RV end-systolic volume index (RVESVi), RV stroke volume index (RVSVi), and RV ejection fraction (RVEF), as well as the outcome of pulmonic valve replacement (PVR). Results 22 patients met the inclusion criteria. Several focal hemodynamic metrics in the main and branch PAs, including WSS steady , taWSS, WSS systole , WSS diastole, and OSI were associated with RV measurements at follow-up, including RVEDVi, RVESVi, and RVSVi. LPA WSS steady,avg , RPA WSS steady,peak , whole vessel OSI avg , and MPA OSI avg were associated with likelihood of PVR. Conclusion CFD-derived hemodynamic variables in the PAs of rToF patients are associated with both PVR and RV remodeling.

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Recent grants

• NIH Grant M01RR000240

  NIH · $6.4M · 2006

• NIH Grant U01HL09815303S1

  NIH · $61k · 2015

• Mouse functional analysis of genes for congenital heart disease

  NIH · $26.5M · 2011–2022

• NIH Grant R01HL074094

  NIH · $2.6M · 2010

• NIH Grant R21HL098844

  NIH · $436k · 2013

Frequent coauthors

• Hugo Ten Cate

  Maastricht University

  1440 shared

• Albert Schinzel

  Liechtenstein Institute

  895 shared

• Deborah Bartholdi

  University of Bern

  890 shared

• Hiroshi Mitsubuchi

  Kumamoto University Hospital

  534 shared

• Kimitoshi Nakamura

  Kumamoto University

  534 shared

• Shiro Matsumoto

  Jichi Medical University

  522 shared

• Fumio Endo

  Tohoku University

  522 shared

• Mario Vaccaro

  University of Messina

  350 shared

Labs

• Elizabeth Goldmuntz LabPI