# Genetics of arrhythmic mitral valve prolapse: large pedigree collection within the UCSF MVP registry

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $775,013

## Abstract

PROJECT SUMMARY
Mitral valve prolapse (MVP) is a common valvulopathy with a strong hereditary component affecting over 7
million individuals in the United States. Every year, up to 1.8% of MVPs will develop sudden cardiac arrest
(SCA) or sudden cardiac death (SCD). In prior studies, SCD/SCA in MVP has either been linked to severe
mitral regurgitation (MR) or to a malignant bileaflet phenotype with mild MR, mitral annular disjunction (MAD)
and abnormal valvular-myocardial mechanics leading to complex ventricular ectopy (ComVE) and/or left
ventricular replacement fibrosis [late gadolinium enhancement or LGE by cardiac magnetic resonance (CMR)
imaging]. We have shown, supported by an ongoing R01, that diffuse fibrosis by CMR/T1 mapping is linked to
increased arrhythmic risk, regardless of bileaflet phenotype, severe MR, or presence of LGE. Hence,
arrhythmic MVP may not be a “pure” valvulopathy, but rather a component of a primary subclinical myopathy.
In addition to mutations in cilia-related genes (DCHS1, TNS1, LMCD1, DZIP1) previously described in
“general” MVP, cardiomyopathy or channelopathy genes (FLNC, LMNA, ALPK3, SCN5A) have been recently
proposed in arrhythmic MVP, albeit in case reports, or GWAS studies with heterogeneous presentations.
Through an ongoing R01 and an expanding MVP registry at our institution, we have identified a total of 14
arrhythmic MVP probands and pedigrees, and 50 sporadic arrhythmic MVP cases. In this administrative
supplement application, we seek to complete whole exome sequencing, arrhythmic characterization, and CMR
in a minority of family members that have yet to undergo these investigations. Our central hypothesis is that
among MVP genetic variants, cardiomyopathy or channelopathy genes act alone or in combination with cilia-
related variants to increase the risk of SCD/SCA in MVP. To test our central hypothesis and accomplish our
overall objective, we propose the following Specific Aims: Aim 1: To identify clinical features and genetic
determinants of arrhythmic risk in MVP SCD/SCA pedigrees, and Aim 2: To test pathogenicity of genetic
variants and understand mechanisms of arrhythmic MVP using protein expression data and cell model assays.
Data obtained through this administrative supplement is essential for better MVP SCD/SCA risk stratification,
thus enabling future prevention of SCD via ICD placement in appropriately selected MVP patients. Use of cell
model assays to validate our genetic findings is essential to understand arrhythmogenesis in MVP patients.
Our proposal is motivated by a recent NHLBI workshop on research opportunities in MVP and the CAROL Act
in memory of a US congressman’s wife who died suddenly from MVP.

## Key facts

- **NIH application ID:** 10850759
- **Project number:** 3R01HL153447-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Francesca N Delling
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $775,013
- **Award type:** 3
- **Project period:** 2020-05-26 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850759

## Citation

> US National Institutes of Health, RePORTER application 10850759, Genetics of arrhythmic mitral valve prolapse: large pedigree collection within the UCSF MVP registry (3R01HL153447-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10850759. Licensed CC0.

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