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

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.

Lmod2 is necessary for effective skeletal muscle contraction

“…All three isoforms robustly promote actin filament nucleation in vitro and Lmod2 and -3 have also been shown to promote elongation of thin filaments in cultured myocytes and in vivo (2)(3)(4)(5)(6)(7). Mutations in all three isoforms are linked to disease in humans with the common underlying pathophysiology of reduced muscle contractility and severe muscle weakness (4,(8)(9)(10)(11)(12)(13). Lmod1 is predominantly expressed in smooth muscle and its deficiency impairs smooth muscle contractility and causes a rare congenital disease called microcolon intestinal hypoperistalsis syndrome (MMIHS) (8).…”

“…Cardiac-specific transgenic overexpression of Lmod2 results in longer thin filaments, enlarged atrial and ventricular lumens, disorganized myofibrils, and eventual heart failure (17). Recently, mutations in LMOD2 have been linked to severe neonatal dilated cardiomyopathy (DCM) in humans (9)(10)(11)(12)(13). To date, seven individuals (from five families) have been identified with pathogenic LMOD2 gene mutations.…”

“…To date, seven individuals (from five families) have been identified with pathogenic LMOD2 gene mutations. Four passed away within a month of birth due to heart failure (9,10), and three received heart transplants at 10 (patient 1), 14 (patient 2), and 7 (patient 3) months of age (11)(12)(13). Limited analysis of skeletal muscle in two of the patients that received transplants via ultrasound (at 1 month old) and quadriceps biopsy (at 4.5 months old) in patient 1 (11) and physical examination (at 9 months and 5 years) in patient 2 revealed no abnormalities (12).…”

KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy

“… 17 To date, DCM‐causing variations in >250 genes have been implicated with the development of DCM, of which the vast majority code for sarcomere proteins, nuclear envelope proteins, cytoskeleton proteins, Z‐band proteins, intercalated disc proteins, ion channel proteins, gap junction channel proteins, RNA‐binding proteins, mitochondrial proteins, and transcriptional factor proteins. 1 , 2 , 3 , 4 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 Additionally, genome‐wide association studies have led to the discovery of many new common variants involved in DCM, in addition to novel rare variants involved in DCM. 33 Nevertheless, the genetic architecture of DCM is highly complex and diverse owing to pronounced genetical heterogeneity, and the genetic determinants underpinning DCM in a large proportion of cases remain to be identified.…”

No April fools in clinical genomics

“…Previously, the role of LMOD2 in dilated cardiomyopathy was unclear, with evidence from a single patient. Via exome sequencing, Yuen et al identify a further sibship with homozygous LMOD2 variants providing further evidence for its role in cardiomyopathy [11]. Wade and colleagues identify deletion of the last 2 exons of FGF10 as a novel molecular genetic cause of lacrimo-auriculo-dental-digital syndrome [12].…”