Genomic basis of phenotypic variability of complex disorders Abstract Recent studies have suggested a class of rare CNVs that are often inherited as well as associated with various complex disorders including intellectual disability, congenital cardiac disease, obesity, epilepsy, autism, and schizophrenia. While these CNVs confer a higher risk for disease, they are not necessarily sufficient to cause disease. This implies a need to consider additional genetic factors that may account for phenotypic variability. Our long-term interests are to understand how a combination of genetic variants can lead to specific clinical outcomes.
The specific aims proposed will help us to identify all forms of genetic variants in individuals with 16p12.1 deletion and to understand the biological mechanisms for variability from functional studies in model systems. Our three specific aims are to: (1) Perform whole genome sequencing (WGS) of 100 families, including an estimated 325 individuals (75 trios and 25 quad families), with at least one affected individual carrying a 16p12.1 deletion, to identify copy-number variants (CNVs), single nucleotide variants (SNVs), and insertion-deletions (INDELs) using a combination of variant-detection algorithms; (2) Prioritize genetic variants for disease and functional association,, perform quantitative phenotyping of families with 16p12.1 deletion, and integrate genetic data with phenotypic data to identify specific patterns of genetic variants contributing to the observed traits; (3) Perform functional studies in model systems to test dosage-sensitivity of Drosophila melanogaster and Xenopus leavis orthologs of 16p12.1 genes using highly sensitive quantitative methods, and assess the effect of a selected ten candidate modifier genes by two locus models. This proposal will aid in identifying biologically valid variants that interact with 16p12.1 genes contributing towards specific phenotypes, which will help in a more accurate diagnosis of specific subtypes of developmental disorders, and provide impetus for targeted treatment strategies.

Public Health Relevance

Genomic basis of phenotypic variability of complex disorders Public health relevance statement This proposal focuses on discovering and characterizing genetic variants that contribute to phenotypic variability in individuals carrying 16p12.1 deletion to aid in understanding the genetic etiology of complex disorders. This work will provide a fundamental understanding of how specific combinations of genetic changes can determine an ultimate clinical outcome, and will develop a novel functional approach to accurately determine the effect of gene dosage alteration.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Krasnewich, Donna M
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Pennsylvania State University
Schools of Arts and Sciences
University Park
United States
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Pizzo, Lucilla; Jensen, Matthew; Polyak, Andrew et al. (2018) Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants. Genet Med :
Iyer, Janani; Singh, Mayanglambam Dhruba; Jensen, Matthew et al. (2018) Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster. Nat Commun 9:2548
Lasser, Micaela; Tiber, Jessica; Lowery, Laura Anne (2018) The Role of the Microtubule Cytoskeleton in Neurodevelopmental Disorders. Front Cell Neurosci 12:165
Jensen, Matthew; Girirajan, Santhosh (2017) Mapping a shared genetic basis for neurodevelopmental disorders. Genome Med 9:109
Girirajan, Santhosh (2017) Missing heritability and where to find it. Genome Biol 18:89