Samya Chakravorty, PhD
Division of Neurology
Department of Pediatrics
Emory University School of Medicine
I am a molecular and human geneticist, and muscle biologist, with training in cardiac/skeletal muscle physiology and genetics of neuromuscular disorders. I am working on developing methods for translation of functional genomics and molecular assays to clinical care for faster, more precise diagnosis and precise, targeted therapies.
Our work is focused to perform inter-disciplinary translational research that will merge basic (research-based) and clinical (ACMG guidelines) genetics to transform our understanding of neurological diseases. Primary disease areas of focus are on neuromuscular disorders (NMDs) and epilepsy. The ultimate goal is to facilitate precise molecular diagnosis, identify candidate biomarkers and to use that information in understanding molecular mechanism. Understanding genotype-genotype correlations in genetic disorders will enable the rational development and testing of novel therapeutics using animal and patient-derived cellular models.
Advanced Diagnostics and Resolving Genotype-Phenotype Correlations in Pediatric and Adult Neuromuscular Disease (NMD)
Even in this genomic era, 60-70% of NMD patients remain undiagnosed mainly due to the burden of genetic variants (mutations) of uncertain significance (VUSs), pathogenic variants in multiple genes, lack of minimally-invasive biomarkers, and unresolved genotype-phenotype correlations. Understanding the functional intricacy and the effect of variants is critical to making the right choice of therapeutic approach for Congenital Muscular Dystrophies (CMD), Limb Girdle Muscular Dystrophies (LGMDs), Dysferlinopathies, Duchenne Muscular Dystrophy (DMD), Spinal Muscular Atrophy (SMA), Pompe disease, and related myopathies, neuropathies, and disorders of neuromuscular junctions. We have developed a tiered algorithm using multiple clinically-driven functional genomic approaches targeting blood biomarkers that increased the diagnostic yield to ~90% in a 400 patient-cohort (both pediatric and adult) of specific NMD-type. We are using an integrated approach using next generation sequencing (NGS), functional genomics such as RNA-Seq and proteomics using mass spectrometry and other targeted functional assays to identify clinical significance of VUSs and genes of uncertain significance (GUSs), identify new disease genes and create a comprehensive map of the NMD muscle genome, transcriptome and proteome, which will aid in choosing the most appropriate and focused precision medicine approach.
Resolving Non-Mendelian (or Neo-Mendelian) Multi-Genic Neuromuscular Disorders
In a recent ongoing large-scale program of NGS DNA panel-sequencing of ~7000 pediatric and adult NMD patients across the US in Emory (~5500) and some outside collaboration, we identified that ~30% of all patients harbor reportable genetic variants in more than one gene showing unusual disease presentations and progressions. Thus they remain undiagnosed without definitive molecular answer and is a significant clinical and financial burden in the field. We hypothesize that synergistic contribution of partial defects in genes and related pathways compound to a larger effect such as in the form of synergistic heterozygosity or digenic/multigenic inheritance. We are currently starting to use omics platform on these patient tissues to understand effects on pathways in this multi-genic cohort and marry it to their unusual clinical features to understand the relative contributions of genes, pathways, and understand mechanisms. This will allow not only enhance diagnostics, but also identify novel biomarkers or newer therapeutic strategies.
Understanding the molecular basis of different type and timing of seizure outcomes in epilepsy is important for developing precision medicine. In addition, significant percentage of childhood and adult epilepsy patients still remain undiagnosed at the molecular level even after clinical genetic testing. We are starting to perform gene-variant discovery of undiagnosed epilepsy children using whole genome sequencing (WGS) to capture all possible disease-causing variants. We are also performing bioinformatics and functional analyses to resolve the gene-pathway network responsible for variable pharmacological response in epilepsy, and to understand the unique nature and timing of spams compared to other seizure types. This approach will aid in biomarker discovery for earlier detection and intervention, and understanding the biological mechanism which may lead to potential novel therapeutic targets.
Clinical Genetics Focus
I am a member and Biocurator of ClinGen Working Group and a member of ClinGen’s Platelet Disorder Variant Curation Expert Panel. I devote a significant portion of my time in analyzing and annotating genetic testing results in genetic diseases, including NMDs and epilepsy, creating and reporting back research reports of genetic testing, transcriptome sequencing reports to patients and physicians, re-classifying variants of uncertain significance (VUSs), reviewing gene and variant annotations according to American College of Medical Genetics and Genomics (ACMG) guidelines and submitting them with de-identified evidence to public databases such as ClinVar, dbSNP, dbGAP, HGVS, HGMD for the global clinical diagnostic and research community to access.