Genetic Basis of Left Ventricular Noncompaction

Abstract

Background: Left ventricular noncompaction (LVNC) is the third most common pediatric cardiomyopathy characterized by a thinned myocardium and prominent trabeculations. Next-generation genetic testing has led to a rapid increase in the number of genes reported to be associated with LVNC, but we still have little understanding of its pathogenesis. We sought to grade the strength of the gene-disease relationship for all genes reported to be associated with LVNC and identify molecular pathways that could be implicated. Methods: Following a systematic PubMed review, all genes identified with LVNC were graded using a validated, semi-quantitative system based on all published genetic and experimental evidence created by the Clinical Genome Resource (ClinGen). Genetic pathway analysis identified molecular processes and pathways associated with LVNC. Results: We identified 189 genes associated with LVNC: 11 (6%) were classified as definitive, 21 (11%) were classified as moderate, and 140 (74%) were classified as limited, but 17 (9%) were classified as no evidence. Of the 32 genes classified as definitive or moderate, the most common gene functions were sarcomere function (n=11; 34%), transcriptional/translational regulator (n=6; 19%), mitochondrial function (n=3; 9%), and cytoskeletal protein (n=3; 9%). Furthermore, 18 (56%) genes were implicated in noncardiac syndromic presentations. Lastly, 3 genetic pathways (cardiomyocyte differentiation via BMP receptors, factors promoting cardiogenesis in vertebrates, and Notch signaling) were found to be unique to LVNC and not overlap with pathways identified in dilated cardiomyopathy and hypertrophic cardiomyopathy. Conclusions: LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.

Left ventricular noncompaction: a disorder with genotypic and phenotypic heterogeneity—a narrative review

“…Arrhythmia gene variants were found in 11%, especially in HCN4 (4%). Rojanasopondist et al sought to systematically analyze and score the strength of all published evidence linking each gene to LVNC, and then verified which molecular pathways are likely to be involved in the pathogenesis of LVNC (18). They identified 189 genes associated with LVNC; 11 were classified as definitive, 21 as moderate, 140 as limited, and 17 were classified as no evidence.…”

Left Ventricular Noncompaction in Children: The Role of Genetics, Morphology, and Function for Outcome

“…As demonstrated by several investigators, the Notch signaling pathway is critical for these developmental processes [ 19 ]. Most recently, two more unique genetic pathways were found in LVNC by genetic pathway analysis in humans: cardiomyocyte differentiation via BMP receptors and factors promoting cardiogenesis in vertebrates [ 20 ]. Quite the contrary was postulated by others, namely that LVNC may not be the result of an arrest in the compaction process at all.…”

“…In fact, to date more than hundred genes were described to be associated with LVNC [ 4 , 20 ]. From all the available literature on possible genetic associations with LVNC the study by Mazzarotto et al [ 40 ].…”

Nucleotide sequence variant of the TPM1 gene in a family with different phenotypes of left ventricular non-compaction

“…Вариант нуклеотидной последовательности гена TPM1 в семье с различными фенотипами некомпактного миокарда левого желудочка Кудрявцева М. М. 1 , Киселева А. В. 1 , Мясников Р. П.…”

“…5 , Драпкина О. М. 1 1 ФГБУ "Национальный медицинский исследовательский центр терапии и профилактической медицины" Минздрава России. Москва; 2 МНОЦ ФГБОУ ВО "Московский государственный университет им.…”