Contributed by: Michael Vitanza
Established in 2022.
In human genome, there are multi-kilobase genomic regions known as copy number variants (CNVs). These can affect gene expression and cause genetic disorders by altering genome organization itself and gene function. Therefore, CNVs can also influence the vulnerability of an individual to disease. In prion disease information regarding CNV penetrance, frequency, and functional implications is still evolving.
Prion disease is an adult-onset neurodegenerative disease seen in three forms: sporadic Creutzfeldt-Jakob disease of unknown cause, inherited via genetic mutations, or acquired through exposure to contaminated tissue, food, or medical equipment. In the inherited form, the prion protein gene (PRNP) is the disease-causing gene. Aside from a few recognized polymorphisms (normal variations in the genome), no additional genetic variables, such as age at onset, have been identified that can explain the differences in the disease penetrance or progression.
We plan to use high density whole genome SNP arrays to discover rare copy-number variation regions in the different regions of the brain (for gain or loss of genes). This will enable us to explore the contribution of CNVs to disease vulnerability. In principle, CNVs could account for a significant component of variation in disease risk. This would be a novel finding and an innovation in the context of prion disease. We aim to discover new genetic risk factors in several subtypes of prion disease using evidence-based approach for genotype-phenotype correlations.
Shashirekha Shetty, PhD
National Prion Disease and Pathology Surveillance Center, Case Western Reserve University, University Hospitals, Cleveland, OH
Dr. Shashirekha Shetty is currently the CLIA and molecular laboratory section director for the National Prion Disease Pathology Surveillance Center (NPDPSC), as well as director of Cytogenetics Laboratory at University Hospitals Cleveland Medical Centre (UHCMC) in the Department of Pathology and Center for Human Genetics. She is an associate professor and a program Director of the Laboratory Genetics and Genomics fellowship program at Case Western Reserve University.
She received her PhD from the University of Mumbai, India. She received her European Diploma in Molecular Cytogenetics from the University of Auvergne, France. She completed her postdoctoral fellowship at the Manitoba Institute of Cell Biology (University of Manitoba, Canada).
Since 2005, she has been working on understanding the influence of copy number variants in the context of neurological disorders. She was introduced to genetics of prion disease during her molecular fellowship in 2016 and has since been involved in the diagnosticsof molecular prion disease.