# Stanford Mendelian Genomics Research Center

> **NIH NIH U01** · STANFORD UNIVERSITY · 2024 · $2,778,468

## Abstract

Rapid advances in genomics have ushered in new opportunities for Mendelian disease discovery and
diagnosis. In the last decade, exome and genome sequencing have moved from the research domain to
clinical practice. These approaches have identified new disease genes and causative variants for ~30% of
individuals suffering from a rare genetic disease. We believe that the systematic application of promising new
genomics assays coupled with innovative computational approaches will foster discovery benefitting the 70%
of symptomatic individuals without a genetic diagnosis. To this end we will apply long-read whole genome
sequencing, RNA-sequencing, epigenomics assays, metabolomics and targeted in vitro and in vivo assays to
evaluate a cohort of undiagnosed individuals suspected to have a Mendelian disorder. Our approach will be
augmented through the development and application of computational strategies enabling improved gene and
phenotype matching, integrative multi-omics analysis, and variant interpretation. This work is expected to
establish a new frontier in Mendelian disease discovery. Our Mendelian Genomics Research Center (MRGC)
team has developed key prior expertise and leadership in the use of diverse state-of-the-art experimental and
computational methods for the diagnosis and discovery of Mendelian disorders. We hypothesize that the next
phase of Mendelian genomics research will be defined by assessing and deploying the most effective ‘omics’
strategies. We propose that ongoing and iterative integration of functional genomics data into the translational
genomics toolkit will significantly increase discovery of new gene and variant disease associations beyond the
capabilities of DNA-sequencing assays alone. To facilitate this, we will comprehensively study 400 individuals
and their immediate family members (N= 900 total) with Mendelian disease where exome sequencing has not
yielded a genetic diagnosis. These represent a select cohort of hard to solve cases intractable to DNA
sequencing to date. In Aim 1, individuals recruited into the study will undergo short-read and long-read whole
genome sequencing, RNA-seq, ATAC-seq and MethylC-seq across multiple commonly used cell/tissue types
as well as metabolomics and lipidomics assays. This dataset will define a holistic view of emerging genomics
approaches for Mendelian disease diagnosis and facilitate evaluation of the relative merits of each approach.
In Aim 2, we focus on computational innovations that will improve integration of these multi-omics data in gene
and variant interpretation by integrating functional genomics outliers and advanced statistical learning
approaches. These methods will be applicable broadly across the MGRC and the world. In Aim 3, we apply
state-of-the-art targeted approaches including massively-parallel reporter assays, induced-pluripotent stem cell
functional genomics, CRISPR screens for modifier genes and engineered mouse models to detect and validate
novel causal va...

## Key facts

- **NIH application ID:** 10837896
- **Project number:** 5U01HG011762-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jonathan Adam Bernstein
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,778,468
- **Award type:** 5
- **Project period:** 2021-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837896

## Citation

> US National Institutes of Health, RePORTER application 10837896, Stanford Mendelian Genomics Research Center (5U01HG011762-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10837896. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*