# Identifying genetic factors that cause and modify CMT (Project 2)

> **NIH NIH U54** · UNIVERSITY OF IOWA · 2022 · $347,555

## Abstract

Abstract
Genetics is at the core of CMT diagnoses, pathophysiology, and preparation for trials and gene therapy
approaches. The latter requires precise genetic diagnosis for each individual patient and genetics will also be
highly informative for long-term outcomes. However, even with 90+ CMT and related genes identified, over
50% of CMT2 patients do not receive a diagnosis today. This gap in heritability has many potential
explanations, including additional CMT genes to be discovered, non-coding mutations, unconventional
variation (i.e. repeat expansions), oligogenic inheritance, and Variants of Unknown Significance. Our long-term
commitment to the genetic modifier study in CMT1A has yielded a genome wide significant association
(GWAS) of SIPA1L2 as the first CMT1A modifier gene. Importantly, this discovery promises a novel strategy to
correct the increased gene dosage of PMP22. The INC has collected 1,700 samples of CMT1A patients and
another 1,000 are expected over the next five years. With new statistical methods and genome sequencing
now available we will bring this unparalleled effort to its full potential by combining all these strengths and
comprehensively define the genetic architecture of CMT1A. We anticipate that some of these risk factors have
effects on other more common types of CMT, such as CMT1B, CMTX, and CMT2A. Over the past funding
period, we have discovered 22+ novel CMT and related genes, including a CMT causing repeat expansion
disease. We will continue this work, but focus on improving our sample and data resources in size and
ancestral diversity. This will be achieved by further expanding data sharing with CMT-ID, AOINC, and the MRC
in the UK. We will develop a CMT genetic data archive and utilize the GENESIS genomic software platform
that has helped to discover most of the above mentioned CMT genes. Finally, in the previous funding cycle we
have created the Inherited Neuropathy Variant Browser (INVB) to collect disease related variation in CMT
genes internationally and provide this information openly to the community. Given our specialized interest in
CMT and related disorders and our international reach, this CMT-focused effort goes far beyond the reach of
NIH ClinVar. We will develop INVB version 2.0 that includes more data, additional correlations, and deeper
information on VUS. Specifically, we propose to (1) Perform an Iterative expansion of modifier studies in
CMT1A and other relatively common CMT subtypes, (2) Build a sustained infrastructure for data sharing and
continued discovery of new CMT genes, and (3) Develop the CMT variant browser 2.0 that will also provide a
phenotype bank for CMT enabling patients and investigators to rapidly obtain diagnostic and de-identified
clinical information on disease causing mutations.

## Key facts

- **NIH application ID:** 10456929
- **Project number:** 5U54NS065712-15
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Stephan Zuchner
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $347,555
- **Award type:** 5
- **Project period:** 2009-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456929

## Citation

> US National Institutes of Health, RePORTER application 10456929, Identifying genetic factors that cause and modify CMT (Project 2) (5U54NS065712-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10456929. Licensed CC0.

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