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

Michaela Yuen1,2, Lisa Worgan3, Jessika Iwanski4

  • 1Kids Neuroscience Centre, The Children's Hospital at Westmead, Westmead, NSW, Australia. michaela.yuen@sydney.edu.au.

European Journal of Human Genetics : EJHG
|January 27, 2022
PubMed

Insights

A novel splice-site variant in the LMOD2 gene causes lethal dilated cardiomyopathy (DCM) in newborns. This genetic defect leads to absent LMOD2 protein, short actin filaments, and severe heart dysfunction.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • Dilated cardiomyopathy (DCM) is a severe heart condition characterized by enlarged ventricles and impaired contractility, often leading to heart failure.
  • Previous research linked leiomodin-2 (LMOD2) gene variants to a rare, lethal form of neonatal DCM.
  • The precise molecular mechanisms underlying LMOD2-associated DCM remain incompletely understood.

Purpose of the Study:

  • To investigate the genetic cause of lethal DCM in two siblings.
  • To elucidate the functional consequences of a novel LMOD2 splice-site variant.
  • To confirm the role of LMOD2 in cardiac development and function.

Main Methods:

  • Whole exome sequencing to identify genetic variants in affected siblings.
  • Pre-mRNA splicing assays and Western blot analysis to assess LMOD2 mRNA and protein expression.
  • Immunostaining of cardiac tissue to examine actin filament structure.

Main Results:

  • Identified a homozygous splice-site variant (c.273+1G>A) in the LMOD2 gene in both siblings.
  • Demonstrated that the variant abrogates canonical LMOD2 mRNA splicing and leads to absence of full-length LMOD2 protein.
  • Observed abnormally short actin-thin filaments in the probands' heart tissue.

Conclusions:

  • The LMOD2 splice-site variant is pathogenic, causing loss of functional LMOD2 protein.
  • Absence of LMOD2 disrupts actin filament organization, leading to severe cardiac contractile dysfunction and neonatal DCM.
  • This study highlights the critical role of LMOD2 in cardiac development and identifies the first splice-site variant associated with DCM.

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