Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant

Michaela Yuen, Lisa Worgan, Jessika Iwanski, Christopher T. Pappas, Himanshu Joshi, Jared M. Churko, Susan Arbuckle, Edwin P. Kirk, Ying Zhu, Tony Roscioli, Carol C. Gregorio, Sandra T. Cooper

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Dilated cardiomyopathy (DCM) is characterized by cardiac enlargement and impaired ventricular contractility leading to heart failure. A single report identified variants in leiomodin-2 (LMOD2) as a cause of neonatally-lethal DCM. Here, we describe two siblings with DCM who died shortly after birth due to heart failure. Exome sequencing identified a homozygous LMOD2 variant in both siblings, (GRCh38)chr7:g.123656237G > A; NM_207163.2:c.273 + 1G > A, ablating the donor 5′ splice-site of intron-1. Pre-mRNA splicing studies and western blot analysis on cDNA derived from proband cardiac tissue, MyoD-transduced proband skin fibroblasts and HEK293 cells transfected with LMOD2 gene constructs established variant-associated absence of canonically spliced LMOD2 mRNA and full-length LMOD2 protein. Immunostaining of proband heart tissue unveiled abnormally short actin-thin filaments. Our data are consistent with LMOD2 c.273 + 1G > A abolishing/reducing LMOD2 transcript expression by: (1) variant-associated perturbation in initiation of transcription due to ablation of the intron-1 donor; and/or (2) degradation of aberrant LMOD2 transcripts (resulting from use of alternative transcription start-sites or cryptic splice-sites) by nonsense-mediated decay. LMOD2 expression is critical for life and the absence of LMOD2 is associated with thin filament shortening and severe cardiac contractile dysfunction. This study describes the first splice-site variant in LMOD2 and confirms the role of LMOD2 variants in DCM.

Original languageEnglish (US)
Pages (from-to)450-457
Number of pages8
JournalEuropean Journal of Human Genetics
Volume30
Issue number4
DOIs
StatePublished - Apr 2022

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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