# Discovery of Novel Genetic Variants Underlying Unexplained Hypertrophic Cardiomyopathy by Whole Genome Sequencing, RNA-seq and iPSC modeling

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $169,560

## Abstract

PROJECT SUMMARY
This proposal describes a five-year plan for Dr. Alireza Haghighi's career development towards becoming an
independent cardiovascular investigator. Currently an Instructor in Medicine and Clinical Molecular Geneticist in
Brigham and Women's Hospital (BWH), and Harvard Medical School (HMS),
Dr. Haghighi's long-term career goals
are to translate genomic research into clinical advances for cardiovascular patients. His career development and
research plan leverages his training in human genetics and the unique training environment of BWH, HMS, and the
Broad Institute that will provide him with new skills in statistics, computational biology, and induced pluripotent stem
cell (iPSC) disease modeling, in order to shed novel insight into the mechanisms underlying hypertrophic
cardiomyopathy (HCM). His career development goals will be achieved through scientific investigation and
collaborations, and supported by mentorship, didactic coursework and conferences. Dr. Haghighi has assembled a
Mentoring and Scientific Advisory Committee that includes world experts in cardiology, and human genetics: Drs.
Christine Seidman (primary mentor), Jon Seidman (co-mentor), Shamil Sunyaev (advisor) and Mark Daly (advisor),
who have mentored countless young investigators to successful independent investigators.
 HCM is the most common inherited cardiovascular diseases and the leading cause of sudden death in
young people. Dominant mutations in sarcomere proteins cause HCM in 30-60% of patients- data that has
enabled mechanistic studies that propel new therapeutic strategies to treat HCM. These opportunities are
profoundly limited in sarcomere-negative (unexplained) HCM patients in whom there is no understanding of how
or why disease emerges. Dr. Haghighi's whole exome sequencing (WES) analyses in genetically unexplained
HCM patients concluded that non-coding variants may play a role in pathogenesis of this disease. This proposal
seeks to define genetic etiologies (with a focus on non-coding variants) for HCM in patients that remain unsolved
after WES sequencing by whole genome sequencing (WGS). To determine the functional impact of newly
identified non-coding variants, Dr. Haghighi will model and characterize prioritized candidate variants in human
isogenic cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs). Using these approaches he
will explore three specific aims that (1) Identify rare variants in non-coding regions of known HCM genes and
prioritized genes in blood and heart tissue samples of unexplained HCM patients by WGS, (2) Define
dysregulated gene expressions and splicing effects of identified variants by RNAseq, and (3) Assess the effects
of prioritized non-coding variants in human iPSCs. By providing fundamental new insights into the functional role
of non-coding variants that may uncover new causes of HCM (thereby improving patient care), these studies will
support NHLBI goals to improve our understanding of the molecular ba...

## Key facts

- **NIH application ID:** 10764235
- **Project number:** 5K08HL150284-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Alireza Haghighi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $169,560
- **Award type:** 5
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764235

## Citation

> US National Institutes of Health, RePORTER application 10764235, Discovery of Novel Genetic Variants Underlying Unexplained Hypertrophic Cardiomyopathy by Whole Genome Sequencing, RNA-seq and iPSC modeling (5K08HL150284-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10764235. Licensed CC0.

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