# Center for Integrated Approached to Undiagnosed Diseases

> **NIH NIH U01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $188,666

## Abstract

Undiagnosed diseases are likely to be determined by genetic, environmental, and developmental factors.
While some undiagnosed diseases will represent novel rare genetic syndromes with monogenic or oligogenic
etiologies and others will reflect rare manifestations of known diseases, many are likely to result from a more
analytically challenging combination of multiple genetic, environmental, and developmental factors. Whole
exome and whole genome sequencing are powerful tools with which to ascertain the genetic contributions to
undiagnosed diseases; however, these methods alone are unlikely to elucidate the basis for many, if not most,
undiagnosed diseases. The central unifying hypothesis of this proposal is that an integrated, network-based,
systems biology approach that incorporates not only genetic variation data, but also gene expression,
metabolomic, proteomic, and exposomic data, along with careful deep phenotyping, will prove to be the most
effective way to identify the pathways and mechanisms responsible for many undiagnosed diseases. To
address the underlying hypothesis, we propose to establish an integrated interdisciplinary research plan for the
Harvard Undiagnosed Disease Network Clinical Site (Harvard UDN-CS) that involves three Specific Aims:
 1) Ascertainment and clinical characterization--we will perform case ascertainment and phenotypic
 characterization for selected rare and undiagnosed disease states in adults and children;
 2) Genomic assessments--we will use patient and family member-derived DNA sequence, transcriptomic
 data (when available), and clinical phenotype information to identify potentially causal DNA sequence
 variants, gene expression variation, and potentially causative pathway derangements; and
 3) Network-based systems biology approach to disease diagnosis--we will integrate other -omic data,
 including metabolomic, proteomic, and exposomic data, along with the candidate genetic variants into
 the comprehensive interactome, and thereby identify diseases or disease pathways in network
 proximity to the involved genes that may help identify potential pathobiological modules relevant to the
 etiology of the undiagnosed disease and potential drug targets that may modify pathophenotype.
We will work toward meeting these specific aims and addressing the overall hypothesis in close collaboration
with the UDN Coordinating Center (UDN-CC) and other clinical sites in the UDN in order to develop and
implement assessment protocols of phenotype, environment, and genotype that will ultimately define the
etiology and treatment of undiagnosed diseases.

## Key facts

- **NIH application ID:** 10696474
- **Project number:** 3U01HG007690-08S2
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Joseph Loscalzo
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $188,666
- **Award type:** 3
- **Project period:** 2014-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10696474

## Citation

> US National Institutes of Health, RePORTER application 10696474, Center for Integrated Approached to Undiagnosed Diseases (3U01HG007690-08S2). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10696474. Licensed CC0.

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