# Pediatric Mendelian Genomics Research Center

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $2,159,760

## Abstract

ABSTRACT
Mendelian conditions, particularly those presenting during childhood, are a major disease burden causing
suffering and taxing the healthcare system. Clinical approaches including exome sequencing have led to a
rapid increase in the number of conditions with known genetic causes and new treatment options for many rare
diseases, but are restricted to finding small coding and splice junction variants, missing most non-coding
variants as well as structural and copy number variants. This challenges interpretation due to the vast number
of variants that must be analyzed for possibly causing a disease.
To accelerate the pace of Mendelian disease gene discovery and clinical implementation, we propose a
Pediatric Mendelian Genomics Research Center (MGRC), leveraging the broad pediatric clinical and
research expertise of Children’s National Hospital and Research Institute in a partnership with Invitae’s
expertise in providing comprehensive and affordable genetic testing. Our Center will unite world class
experts combining basic and translational research with innovative approaches to phenotyping, variant
identification and functional investigation of both coding and non-coding sequence changes with the goals of
discovering novel Mendelian gene variations and identifying variants not detected on current sequencing
pipelines, disambiguating uncertain variants into disease-causing versus benign categorizations, and sharing
information by working collaboratively with the MGRC community. To answer these challenges, this proposal
will address the following Specific Aims:
Aim 1: Identify novel causes of Mendelian conditions - Discover: Our center will enroll patients with likely
Mendelian diseases and previously non-diagnostic tests (2,600 samples per year) then systematically re-
analyze whole genomes augmented with long read sequencing, optical mapping, and RNA-seq.
Aim 2: Reclassify uncertain variants and investigate the mechanisms of undiagnosed Mendelian
conditions - Disambiguate: Uncertain variants and candidate genes will be further investigated using whole
transcriptome analysis, RNA-seq, CRE-seq, and functional modeling.
Aim 3: Communicate research results to enable translational research on new and rare Mendelian
conditions - Disseminate: Our center is committed to data sharing and dissemination and will ensure that
data is shared with the entire MGRC community through the data coordinating center. Through our industry
partnership, clinically valid pipelines will be rapidly scaled for clinical implementation globally.
Our overall approach provides an efficient and direct path to diagnosis for patients affected with undiagnosed
Mendelian conditions, promotes gene discovery and reclassification of Variants of Uncertain Significance
through a combination of innovative approaches, and will allow individuals, families and healthcare providers to
improve the management of disease.

## Key facts

- **NIH application ID:** 10794131
- **Project number:** 7U01HG011745-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Eric J. Vilain
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,159,760
- **Award type:** 7
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794131

## Citation

> US National Institutes of Health, RePORTER application 10794131, Pediatric Mendelian Genomics Research Center (7U01HG011745-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10794131. Licensed CC0.

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