# Collaborative Research to Explore Genetic Variation and Phenotypic Spectrum of Elastin and Related Genes

> **NIH NIH U01** · GEISINGER CLINIC · 2021 · $600,686

## Abstract

Summary
In the past, new diseases were delineated when clinicians brought together a cohort of individuals with similar
phenotypic characteristics. They then performed genetic testing and looked for shared genetic changes among
the affected cohort. While this method proved successful in some cases, discovery was limited to disorders
with relatively few genes and highly distinctive presentation. Since the advent of exome sequencing,
physicians have become increasingly aware of the wide spectrum of variability of clinical features associated
with previously known genes, with the actual manifestations attributable to a genetic variation being far greater
than what was previously anticipated--the proverbial, “iceberg effect.” Overcoming these challenges requires a
new approach. Instead of starting with the defined phenotype, we propose starting at the gene and working our
way forward to identify the full spectrum of phenotypes that can arise from these genetic variations. Such work
requires high numbers of well-phenotyped and genotyped samples, as well as the expertise to appropriately
evaluate patients of interest. This application brings together two institutions with the experience and capability
to do just that. The Geisinger Health System maintains extensive medical records and genotype and sequence
data on more than 141,000 participants enrolled in the MyCode Community Health Initiative and has the
expertise to mine those records and genomic sequences for meaningful and medically relevant associations.
The NIH has expertise in the deep phenotyping and discovery in rare disease. For proof of principle that this
gene-first strategy works, we are beginning our analysis into elastic fiber mediated connective tissue disease,
an area with which our NIH collaborators have significant expertise. Previous literature linked changes in
elastic fiber genes to defects in aortic diameter and tortuosity, lung changes such as emphysema and skin
changes including laxity with more recent work suggesting connections to more common phenotypes such as
hypertension, intracranial aneurysm, and chronic obstructive pulmonary disease. Our goal is to define all
phenotypes, rare and common, associated with elastic fiber disease and to investigate the mechanism by
which variation in these genes produces phenotypes in order to develop novel treatment strategies. In order to
achieve this goal, we have developed two specific aims combining the strengths of Geisinger and the National
Institutes of Health investigators. Aim 1. A) Screen an unselected population for variants in elastin and other
elastic fiber genes and B) correlate with phenotypic features mined from the electronic health record. Aim 2:
Identify previously unidentified phenotypes in patients with known and novel damaging variants in elastic fiber
genes through deep phenotyping and disease modeling in vitro functional analysis. Collaboration between the
two institution's diverse and multidisciplinary teams will i...

## Key facts

- **NIH application ID:** 10129419
- **Project number:** 5U01HL146188-02
- **Recipient organization:** GEISINGER CLINIC
- **Principal Investigator:** Beth A Kozel
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $600,686
- **Award type:** 5
- **Project period:** 2020-03-20 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129419

## Citation

> US National Institutes of Health, RePORTER application 10129419, Collaborative Research to Explore Genetic Variation and Phenotypic Spectrum of Elastin and Related Genes (5U01HL146188-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129419. Licensed CC0.

---

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