# Calcium Release Channel Deficiency Syndrome

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $403,500

## Abstract

PROJECT SUMMARY
Potentially lethal cardiac channelopathies associated with pathogenic variants in the RYR2-encoded
cardiac ryanodine receptor type 2 (RyR2)/calcium release channel (CRC) are the pathogenic basis for
a significant portion of autopsy-negative sudden unexplained death in the young (SUDY). RYR2 gain-
of-function (GOF) pathogenic variants account for 60% of autosomal dominant catecholaminergic
polymorphic ventricular tachycardia (CPVT1), a potentially lethal heritable arrhythmia syndrome that
classically manifests as exercise-induced syncope, sudden cardiac arrest (SCA), or sudden cardiac
death (SCD). In 2020, we discovered a novel RYR2 loss-of-function (LOF) mechanism that we have
termed calcium release channel deficiency syndrome (CRCDS). We identified a novel homozygous
duplication (RYR2-DUP) involving ~26,000 bp of intergenic sequence, RYR2’s 5’UTR/promoter region,
and exons 1-4 of RYR2 that is responsible for highly penetrant, exertion-related SCA/SCD in the Amish
community without an overt phenotype to suggest RYR2-mediated CPVT1. Unlike typical CPVT1,
individuals homozygous for the RYR2 duplication have displayed typically only intermittently prolonged
QT intervals or prominent U-waves and typically had completely normal exercise/epinephrine stress
tests and normal 24-hour Holter monitoring. Thus, cardiologic tests, such as ECG, stress testing, and
echocardiogram, are currently unable to reliably identify or further risk stratify family members likely to
be homozygous for the RYR2 duplication. Given the potentially lethal nature of these inheritable RYR2-
CRCDS variants and the lack of a robust and measurable clinical phenotype, it is vitally important to
better understand the spectrum and contribution of CRCDS-associated RYR2 variants in SUDY and to
determine the underlying disease-associated mechanisms in patient-specific re-engineered heart cell
models using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Here, we propose to
1) determine the frequency of CRCDS due to RYR2 coding region, non-coding region, and structural
variants (SVs) in SUDY and 2) develop an international registry for CRCDS to identify
genotype/phenotype correlates to assist in clinical diagnosis and management of patients with CRCDS.
3) determine the relative contribution of CRCDS (LOF)-associated RyR2 variants versus CPVT1
(GOF)- variants in SUDY using functional studies, 4) develop a function-based iPSC-CM platform for
RyR2 VUS resolution, and 5) determine the compensatory mechanisms related to loss of RYR2
transcript/RyR2 protein expression and function as it relates to calcium handling components and heart
cell function during early cardiac development.

## Key facts

- **NIH application ID:** 10771449
- **Project number:** 1R01HL171023-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** MICHAEL JOHN ACKERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $403,500
- **Award type:** 1
- **Project period:** 2024-06-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771449

## Citation

> US National Institutes of Health, RePORTER application 10771449, Calcium Release Channel Deficiency Syndrome (1R01HL171023-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10771449. Licensed CC0.

---

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