Genetic Discovery in Rare Diseases pilot grant awardees announced

Tuesday, August 3, 2021
Headshots from left to right: Debra Silver, PhD, Andrew Landstrom, MD, PhD, Derek Peters, PhD

Awardees for Genetic Discovery in Rare Diseases pilot grant: Debra Silver, Andrew Landstrom and Derek Peters

The Duke School of Medicine Precision Genomics Collaboratory and the Duke Center for Combinatorial Gene Regulation, an NIH Center of Excellence in Genome Sciences, offered pilot grants to investigators to study the role of whole exome and whole genome sequencing in human cohorts with rare diseases.

These grants were open to investigators at all stages in their careers. We awarded $20,000 grants to three projects

Congratulations to the Awardees!

Awardee: Debra Silver, PhD | Associate Professor, Department of Genetics and Microbiology

Project Title: Using cortical human organoids to model Richieri-Costa-Pereira Syndrome

Human hypomorphic mutations in the RNA-binding protein EIF4A3 cause Richieri-Costa-Pereira syndrome (RCPS), a rare autosomal recessive craniofacial disorder associated with learning impairment and microcephaly. The mutation has been mapped to a specific region in the genome, but, how these mutations cause neurological deficits remains poorly understood. To address this gap, our lab has generated and characterized mouse models and patient cell lines to evaluate EIF4A3 function. The discoveries we have already made have given us foundational information regarding how EIF4A3 mutations may cause neurological disease, including implicating relevant  cell types, cellular processes, and transcriptomic targets. With this grant, we will use our unique tools and expertise to characterize brain development in RCPS patient-derived organoids. Our goal is to establish a new model of RCPS and discover new mechanisms by which the EIF4A3 mutation causes neurological disease.


Awardee: Andrew Landstrom, MD, PhD | Assistant Professor, Departments of Pediatrics and Cell Biology

Project title: Identifying non-coding variants in genotype-unknown youthful sudden unexplained deaths

Sudden unexplained death in the young (SUDY) is defined as a sudden death in a seemingly healthy individual under 40 years old. Three decades of research into SUDY has identified variants in genes encoding cardiac ion channels and channel regulatory proteins that develop lethal and heritable arrhythmias (channelopathies). Given the youthful age at presentation, non-genetic causes of sudden cardiac arrest, such as acquired heart disease, are unlikely. Our goal is to leverage genome sequencing in SUDY to identify novel genetic mechanisms, or loci,  associated with sudden death-predisposing channelopathies. We hypothesize that genetically sequencing elusive SUDY cases will identify candidate genetic variants in the non-coding genome, predominantly deep intronic variants or regulatory regions of known SUDY-associated genes.


Awardee: Derek Peters, PhD | Postdoctoral Fellow, Department of Cell Biology

Project Title: Connecting peripheral artery disease-associated genetic variation to cell type-specific cis-regulatory elements in human skeletal muscle

Genetic and environmental factors contribute to the development of peripheral artery disease (PAD), which effects approximately 200 million people worldwide. Despite existing therapies, critical limb ischemia - a severe form PAD - is associated with a 15-20% amputation rate at one year, highlighting the need for new treatment strategies. Studies have uncovered genetic variants in noncoding regions of the genome that are associated with PAD, although translating these findings into novel disease insight is challenging. Our research project will apply single cell ATAC sequencing to comprehensively catalog candidate gene regulatory elements across the genome in disease-relevant skeletal muscle tissue from PAD patients. We will analyze this data using computational biology methods to predict the gene regulatory effects of disease-associated noncoding variants. If successful, this study will provide insight into the function of PAD-associated genetic variants and serve as a foundation for the discovery of new disease mechanisms and much-needed therapeutic targets for critical limb ischemia.