# Resources for Comparative Mendelian Disease Genomics

> **NIH NIH R24** · JACKSON LABORATORY · 2021 · $792,183

## Abstract

PROJECT SUMMARY
 Approximately 20-30 million Americans are affected by Mendelian genetic disorders with broad clinical
consequences including congenital heart disease, congenital bone diseases, inherited skin diseases,
hereditary neurological disorders, hereditary cancers, and others. Over the last several years, high-throughput,
whole-exome sequencing has been used for molecular diagnosis and as a research tool for discovery of new
disease-causative gene(s). Since the first successful application of this technology six years ago, the
fundamental genetic bases for over 100 Mendelian diseases have been identified. Despite these advances, the
clinical yield for human Mendelian disease by whole-exome sequencing is less than 40%. In contrast to these
clinical cases, the discovery of Mendelian disease genes in mice is powered by genetically defined inbred
strain backgrounds, large consanguineous pedigrees for segregation analysis, and disease modeling through
the use of exciting new CRISPR/Cas9 approaches and more traditional genetic engineering techniques. With
these allied technologies, the application of whole-exome sequencing in recent years has increased the rate of
mutation discovery in mouse by nearly ten-fold. Yet, the success rate for Mendelian disease gene discovery in
the mouse is only slightly higher than 50 percent. Possible limitations of whole-exome sequencing for disease
gene discovery in mouse include shortcomings of variant calling tools, insufficient data resources describing
`normal' genome variation, and the likely existence of structural variants that escape detection by exome-
sequencing. With the promise of exploring and surmounting these limitations, our long-term goal is to create
genomic resources that will facilitate functionalization of naturally occurring variation by employing forward
genetic discovery and reverse genetic validation. More specifically, the objectives of this project are to continue
to tackle the problem of robust discovery and functional validation of variants that cause Mendelian disease
phenotypes in mice with an emphasis on those variants that escape detection by exome sequencing. We will
harness newly affordable, third-generation, long-read sequencing technologies for the discovery of structural
variants (SVs); and further develop pipelines that integrate these new datatypes into a data-driven framework
formouse variant interpretation and candidate gene prioritization that is available to the research community.
Finally, we will take advantage of new high throughput in vivo, CRISPR-based engineering and phenotyping to
prove disease-causation from among a subset of our most interesting and relevant candidate genes.

## Key facts

- **NIH application ID:** 10173933
- **Project number:** 5R24OD021325-06
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** DAVID ERIC BERGSTROM
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $792,183
- **Award type:** 5
- **Project period:** 2020-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173933

## Citation

> US National Institutes of Health, RePORTER application 10173933, Resources for Comparative Mendelian Disease Genomics (5R24OD021325-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10173933. Licensed CC0.

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