LMOD2-related dilated cardiomyopathy presenting in late infancy

Abstract

Leiomodin-2 (LMOD2) is an important regulator of the thin filament length, known to promote elongation of actin through polymerization at pointed ends. Mice with Lmod2 deficiency die around 3 weeks of age due to severe dilated cardiomyopathy (DCM), resulting from decreased heart contractility due to shorter thin filaments. To date, there have been three infants from two families reported with biallelic variants in LMOD2, presenting with perinatal onset DCM. Here, we describe a third family with a child harboring a previously described homozygous frameshift variant, c.1243_1244delCT (p.L415Vfs*108) with DCM, presenting later in infancy at 9 months of age. Family history was relevant for a sibling who died suddenly at 1 year of age after being diagnosed with cardiomegaly. LMOD2-related cardiomyopathy is a rare form of inherited cardiomyopathy resulting from thin filament length dysregulation and should be considered in genetic evaluation of newborns and infants with suspected autosomal recessive inheritance or sporadic early onset cardiomyopathy.

Keywords: LMOD2; autosomal recessive disease; dilated cardiomyopathy; loss of function variant; short thin filament length.

Figure 1:

A) Pedigree suggestive of autosomal recessive inheritance pattern of LMOD2-related cardiac disease in the family. The sibling of the patient (IV-3) died at 12 months of age in an emergency room, hours after being diagnosed with cardiomegaly. Consanguinity status is unknown. B) Sanger sequencing confirming a homozygous deletion of CT at c.1243_1244 in the proband, compared to the reference sequence (above) and to the sequences of the proband’s mother and father (below), which show a heterozygous deletion of CT at c.1243_1244.

Figure 2:

A) Gross photo of opened left ventricle in explanted heart. B) The ventricular interstitium is mildly expanded with thin fibrous bands (Masson trichrome stain, scale bar = 100 microns). C) The normal left ventricular endocardium is above. Enlarged, darkly stained, hyperchromatic nuclei with perinuclear clearing reflect moderate myocyte hypertrophy (hematoxylin & eosin stain, scale bar = 50 microns). D) Electron microscopy of a left ventricular myocyte with grossly normal mitochondria (*) and degenerative Z-band streaming across a sarcomere (arrow). An intercalated disc (arrowheads) is along the left margin (scale bar = 1 micron).