About

Rebecca D Ganetzky, M.D., is an Associate Professor of Pediatrics (Human Genetics) at the Children's Hospital of Philadelphia, within the Department of Pediatrics. She holds a B.A. in Biology and Computer Science from Oberlin College, graduating Magna Cum Laude in 2005, and earned her M.D. with Special Qualifications in Biomedical Research from the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2010. Her research focuses on neurodevelopmental and genetic disorders, with particular attention to mitochondrial diseases and neurodevelopmental proteasomopathies. She has contributed to understanding the genotypic and phenotypic landscape of mitochondrial DNA deletion syndromes, as well as investigating the neuronal role of proteasomal ATPase subunit genes in neurodevelopmental disorders. Dr. Ganetzky's work involves integrating genomic analysis and clinical research to improve diagnosis and understanding of rare genetic conditions affecting neurodevelopment.

Research topics

• Medicine
• Family medicine
• Pediatrics
• Biology
• Pathology
• Genetics

Selected publications

• Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation

  Science Advances · 2026-04-15

  articleOpen access

  Diagnosing rare genetic diseases remains a major challenge despite widespread clinical testing. Long-read RNA sequencing (RNA-seq) offers a powerful approach to capturing the effects of genetic variants on the transcriptome, yet challenges with sequencing coverage, cost, tissue selection, and scalability have limited its clinical adoption. To address this, we developed STRIPE (Sequencing Targeted RNAs Identifies Pathogenic Events), a targeted long-read RNA-seq-based strategy for rare disease diagnosis and variant interpretation. STRIPE enables deep sequencing of full-length transcripts for any customized disease-specific gene panel such that a wide range of clinically informative readouts, including transcript aberrations and sequence variants, can be detected at haplotype-level resolution. Applying STRIPE to 88 individuals spanning two major rare disease groups, we accurately reidentified known pathogenic variants and revealed their transcript consequences, including many unexpected ones. For 8 of 15 splice site region variants, we observed more complex RNA processing defects beyond single exon skipping or cryptic splice site activation. Notably, we find that donor splice site variants frequently activate cryptic intronic polyadenylation sites, leading to premature transcript termination. Leveraging unique strengths of long-read RNA-seq, STRIPE also resolved variants of uncertain significance and uncovered disease-causing variants in five previously undiagnosed individuals. Overall, STRIPE is a powerful, adaptable, and scalable strategy with broad potential to improve clinical variant interpretation and advance genetic diagnosis of rare diseases.

  PublisherDOI

• Selection of Genetic Conditions for Multi-State Genomic Newborn Screening in BEACONS-NBS

  medRxiv · 2026-03-25

  articleOpen access

  Abstract Introduction BEACONS-NBS (Building Evidence and Collaboration for GenOmics in Nationwide Newborn Screening) is the first research study to integrate whole genome sequencing into newborn screening (NBS) across multiple U.S. states and territorial public health laboratory programs (PHLPs). We developed a list of conditions for screening. Methods We designed inclusion criteria and assembled an initial condition list from published resources. The list was revised by clinical experts, molecular geneticists, genetic counselors, PHLPs, rare disease advocacy organizations, the BEACONS-NBS Community Advisory Board, and project leadership from the National Institutes of Health. For each condition, we provided a rationale for early detection, diagnostic signs or biomarkers, and treatments or surveillance strategies. Results The BEACONS-NBS condition list includes 777 conditions associated with 743 genes, one copy number variant, and two aneuploidies and is larger than those used in other genomic NBS research studies in the U.S. and United Kingdom. Most conditions are inborn errors of immunity (37.2%), inherited metabolic disorders (18.7%), or endocrine conditions (18.1%). Nearly all conditions (93.3%) can be confirmed using a non-genetic test. Discussion BEACONS-NBS has established a condition list for implementation across multiple state and territorial PHLPs, enabling the prospective evaluation of feasibility of population-wide genomic NBS.

  PublisherOA PDFDOI

• The genotypic and phenotypic landscape of PDHA1-related pyruvate dehydrogenase complex deficiency

  Open MIND · 2026-01-29

  articleOpen access

  This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015 - SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151/461, 33%). Neonatal or infantile (405/529, 77%) presentations were most frequent, with pre/perinatal abnormalities reported in 47% (159/342). FS/N variants in NMD-predicted region 3.9 (95% Confidence Interval (CI) 1.54-11.04) times increased the odds of fetal findings. Females presented significantly earlier (2 months, interquartile range (IQR) 7.0, n = 224) than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation (odds ratio (OR) 3.01 (95% CI 1.279-7.616) when harboring FS/N variants in NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex (hazard ratio (HR) 3.3 (95% CI 1.95-5.62)), neonatal presentation (HR 5.5 (95% CI 2.17-14.09)), FS/N variants in NMD-predicted region (HR 4.0 (95% CI 1.78, 9.16)), and splice variants (HR 2.3 (95% CI 1.15, 4.59)). More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties, and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four percent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds a substantial improvement to counselling.

  OA PDFDOI

• Advancing precision care in pregnancy through a treatable fetal findings list

  The American Journal of Human Genetics · 2025-04-09 · 7 citations

  reviewOpen access
  PublisherOA PDFDOI

• Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies

  Nature Communications · 2025-11-26 · 2 citations

  articleOpen access

  Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies.

  PublisherOA PDFDOI

• B-182 Evaluating Clinical Biochemical Diagnostic Approaches for Mitochondrial Diseases

  Clinical Chemistry · 2025-10-01

  articleOpen accessSenior author

  Abstract Background Mitochondrial diseases are a diverse group of inherited disorders resulting from defects in mitochondrial function, caused by mutations in either nuclear or mitochondrial DNA. These diseases may affect multiple organ systems, particularly those with high energy demands, such as the liver and muscles. Clinical presentations vary widely, from mild to severe, and may include organ failure, muscle weakness, and neurological deficits. Diagnosing mitochondrial diseases is challenging and typically involves clinical evaluation, genetic testing, biochemical analysis, and imaging. While genetic testing, such as whole-exome sequencing, is the gold standard for identifying pathogenic mutations, its high cost and limited availability can restrict patient access. Muscle biopsies, which are crucial for examining mitochondrial structure and function, are invasive procedures. In contrast, biochemical assays are less invasive, requiring only blood samples, and can assess mitochondrial function and cellular respiration abnormalities. Currently available tests include growth differentiation factor 15 (GDF15) and lactate, along with newer markers such as alpha-hydroxybutyrate (AHB) and the ketone body ratio, both measured via liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The latter marker is a measurement of the beta-hydroxybutyrate and acetoacetate ratio (BHB/AcAc) and reflects the NADH/NAD+ ratio, which is altered in mitochondrial disease but difficult to measure directly. Despite the availability of these assays, diagnosing mitochondrial diseases remains difficult. This study evaluates the performance of these biochemical markers, individually and in combination, to improve diagnostic approaches. Methods Serum or plasma levels of GDF15, lactate, AHB, and the BHB/AcAc ratio were analyzed in over 600 subjects using enzyme-linked immunosorbent assay (GDF15), colorimetric methods (lactate), and LC-MS/MS (AHB and BHB/AcAc). Subjects were categorized into mitochondrial patients (MP) and non-mitochondrial patients (Non-MP) based on chart reviews and genetic testing, excluding the biochemical tests under study. Results Preliminary results show that lactate, AHB, and the BHB/AcAc ratio are significantly higher in the MP group compared to Non-MP subjects, with false-discovery corrected P-values of 1.7E-6, 2.0E-6, and 3.0E-14, respectively. To rule out dietary influences, such as ketogenic diets or fasting, subjects with these conditions were excluded. The BHB/AcAc ratio remained significantly elevated (P = 6.9E-13) in the MP group, suggesting the elevation is not diet-related. GDF15 did not show a significant difference, though sample size discrepancies might have influenced this result. Conclusion Initial findings indicate that the BHB/AcAc ratio is a promising biomarker for distinguishing between mitochondrial and non-mitochondrial patients. Further research is needed to validate these results and refine diagnostic protocols for mitochondrial diseases.

  PublisherOA PDFDOI

• VPS45 Deficiency with Features of Hemophagocytic Lymphohistiocytosis and Progressive Neurologic Involvement

  Journal of Human Immunity · 2025-04-25

  articleOpen access

  Background Biallelic mutations in VPS45 disrupt endosomal protein trafficking, leading to a rare immunodeficiency syndrome characterized by neutrophil dysfunction, with fewer than 40 cases reported. Key features of the condition include neutropenia, recurrent infections, hepatosplenomegaly, nephromegaly, and myelofibrosis. Neurodevelopmental abnormalities, such as global developmental delay, hypotonia, nystagmus, and cortical blindness, have been associated with a specific variant c.712G>A; p.Glu238Lys. Here we present a case with presumed familial hemophagocytic lymphohistiocytosis (HLH) in infancy and progressive neurological symptoms. Case Presentation The patient is a 15-year-old female, who initially presented at 4 weeks of age with severe mastoiditis. She was found to have poor NK cell function, perforin deficiency, and neutropenia. Bone marrow biopsy showed toxic granulation and cytoplasmic vacuolation in some neutrophils. Few histiocytes and no hemophagocytes were seen. She underwent bone marrow transplant (BMT) at 4 months old due to presumed HLH and a history of a brother with HLH who died from an infection post-BMT. She has a history of global developmental delay, dysgraphia, ADHD, primary ovarian insufficiency, multiple fractures, atypical bony development in the feet, and hypercholesterolemia. On examination, she has short stature, facial dysmorphism, atypical dentition, nystagmus, choreiform movements, and gait ataxia. Brain imaging at 10 years of age showed basal ganglia and subcortical white matter calcifications in the frontal lobes. Diagnostic Workup Extensive genetic testing, including genome sequencing and mitochondrial DNA sequencing, was negative. Research-based reanalysis revealed novel biallelic VPS45 missense variants (c.652C>T; p.Arg218Cys and c.1157G>A; p.Arg386His), confirmed by Sanger sequencing. Parental testing demonstrated the variants were inherited in trans from unaffected carriers and were also found in the deceased brother’s exome data. Discussion While a specific variant (p.Glu238Lys) has been linked to neurological symptoms in VPS45 deficiency, it was absent in our case. The patient’s progressive neurological phenotype, including chorea, basal ganglia, and subcortical white matter calcifications, suggests further phenotype expansion. The overlap with HLH and post-BMT complications underscores the diagnostic and therapeutic complexities, emphasizing the need for further research into VPS45-related pathophysiology and its clinical implications. Conclusion This case expands the understanding of VPS45 deficiency by highlighting pronounced neurological involvement, which appears more striking in our proband.

  PublisherDOI

• An Unusual Cause of Hexokinase 1 Deficiency—Case Report

  eJHaem · 2025-08-01

  articleOpen access

  ABSTRACT Introduction Molecular analysis of red cell disorders has revolutionized diagnosis, however, there remain challenges. Main Symptoms This patient presented with hemolytic anemia in the newborn period. He required chronic transfusions to maintain his hemoglobin level until 6 years of age. A splenectomy was performed at 3 years of age. Main Diagnoses Using whole genome sequencing, we were able to identify a duplication upstream of the red cell promoter of HK1 . Long‐read RNA sequencing established aberrant expression off of this promoter. Conclusions These non‐coding variants remain challenging to identify. His promoter duplication may have a founder effect in South Asia.

  PublisherOA PDFDOI

• Single large-scale mitochondrial DNA deletion syndromes: scientific and family conference optimizes the collection of rare disease research outcomes

  Orphanet Journal of Rare Diseases · 2025-08-04

  articleOpen accessSenior author

  BACKGROUND: The SLSMDS Research Network is a collaborative network comprising patient advocates, researchers, clinicians, and affected families seeking to improve outcomes for individuals with single large-scale mitochondrial DNA deletion syndromes (SLSMDS). Building off of jointly developed research infrastructures, including a patient registry and natural history study, advocates and clinicians cohosted the SLSMDS Family and Scientific Conference, enabling the collection of patient data from an ultra-rare and geographically dispersed patient population. Here we describe the data collection procedures for single-time point laboratory assessments and patient reported outcomes for a subset of individuals with SLSMDS. RESULTS: Utilizing a reproducible model of rare disease data collection, we expand our understanding of the common psychiatric manifestations, describe variability in terms of self-care and quality of life, and emphasize potential biomarkers for individuals with SLSMDS. CONCLUSION: Our study describes how efficient patient-researcher partnerships can develop and sustain novel mechanisms to collect rare disease data, improve our understanding of the natural history of these disorders, and support development of future treatments.

  PublisherOA PDFDOI

• Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8

  Neurology · 2025-03-20 · 15 citations

  articleOpen access

  BACKGROUND AND OBJECTIVES: cause incurable mitochondrial syndromes encompassing a wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI. Typically, higher levels of mtDNA variants lead to more severe symptomatology although even individuals with similar mtDNA mutational loads exhibit high clinical variability. Hence, the establishment of potential therapeutics is currently challenging. In this article, we present an international multicenter study designed to provide a retrospective natural history of patients with MT-ATP6/8 deficiency and to identify primary and secondary end points for future clinical trials. METHODS: defects were collected and analyzed from Italian, German, US, and Spain national reference centers through ethical committee-approved mitochondrial patients' national registries or local programs. RESULTS: value = 0.0349) in the survival of infantile and pediatric patients compared with adult patients, although only 8% of patients were not alive at the last follow-up. The CNS was the most frequently affected tissue (93%), followed by the muscle (75%), eye (46%), and heart (18%). Brain MRI showed isolated Leigh-like lesions (58%), Leigh-like lesions and cortical and/or cerebellar atrophy (15%), isolated cerebellar atrophy (10%), and other lesions (21%). At the last follow-up, 11% of patients were wheelchair-bound. Metabolic acidosis or acute deterioration complicated the clinical course in ≅55% of early-onset patients. Molecular genetics studies identified 26 pathogenic variants (6 of them novel). Reduced citrulline levels and increased alanine and lactate levels were reported in 56%, 49%, and 71% of patients, respectively, suggesting their role as potential biomarkers. DISCUSSION: Our results define a more accurate classification based on the age at onset for MT-ATPase deficiency and provide fundamental clinical and biochemical data for disease management.

  PublisherOA PDFDOI

Recent grants

• Medical Genetics Research Training Grant

  NIH · $8.9M · 1997–2027

• Characterizing Cell and Zebrafish Models of Mitochondrial Complex V Deficiency

  NIH · $892k · 2017–2022

Frequent coauthors

• Marni J. Falk

  94 shared

• Amy Goldstein

  University of Pennsylvania

  52 shared

• Zarazuela Zolkipli‐Cunningham

  Children's Hospital of Philadelphia

  38 shared

• Colleen Muraresku

  Children's Hospital of Philadelphia

  34 shared

• Can Fıçıcıoğlu

  27 shared

• Elizabeth M. McCormick

  University of Pennsylvania

  25 shared

• Rebecca C. Ahrens‐Nicklas

  Children's Hospital of Philadelphia

  23 shared

• Chaya N. Murali

  Baylor College of Medicine

  22 shared