Recessive ciliopathy mutations in primary endocardial fibroelastosis: a rare neonatal cardiomyopathy in a case of Alstrom syndrome
Abstract
Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1943delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband’s dermal fibroblasts confirmed the impact of the novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFβ signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 13, 2021
- Source ID
- 10.1007/s00109-021-02112-z
Entities
People
- Aaron Nagiel
- Ascia Eskin
- Atsushi Nakano
- Fabiola Quintero-rivera
- Gary Satou
- Glen S. Van Arsdell
- Gregory A Fishbein
- Juan C. Alejos
- Lee-kai Wang
- Leigh C. Reardon
- Marlin Touma
- Meena Garg
- Myke Federman
- Nancy Halnon
- Negar Khanlou
- Reshma Biniwale
- Ryan J. Schmidt
- Stacy Pineles
- Stanley F. Nelson
- Steven L. Lee
- Viviana M. Fajardo
- Wayne W. Grody
- Xuedong Kang
- Yan Zhao
- Zubin Mehta
Organizations
- American Heart Association
- United States Department of Defense