# Genomic basis of phenotypic variability of complex disorders

> **NIH NIH R01** · PENNSYLVANIA STATE UNIVERSITY, THE · 2020 · $538,435

## Abstract

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.

## Key facts

- **NIH application ID:** 9847974
- **Project number:** 5R01GM121907-04
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** Santhosh Girirajan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $538,435
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847974

## Citation

> US National Institutes of Health, RePORTER application 9847974, Genomic basis of phenotypic variability of complex disorders (5R01GM121907-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9847974. Licensed CC0.

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