Submission Details

Autosomal dominant

04/08/2019

The LAMA4 gene is located on chromosome 6 at 6q21 and encodes laminin subunit alpha 4. Laminins are a major component of basement membranes, and laminins containing α4 subunits are highly expressed in the microvasculature, cardiomyocyte sarcolemma, and cardiac and skeletal muscle. Laminins serve both structural and signaling roles and have been implicated in a diverse array of cellular functions such as cell adhesion and differentiation. LAMA4 was first reported in relation to an autosomal dominant dilated cardiomyopathy in 2007 (17646580: Knöll et al. 2007). At this time, evidence supporting this gene-disease relationship is limited to experimental data. Heterozygous variants in the LAMA4 gene have been reported in a small number of individuals with dilated cardiomyopathy (17646580: Knöll et al. 2007; 26406308: Marston et al. 2015), but none of these variants had sufficient evidence for disease causality. More recently, heterozygous LAMA4 variants have been reported in cases with possible alternative molecular bases for disease (25979592: Waldmüller et al. 2015; 29253866: Klauke et al. 2017; 30165862: Lu et al. 2018; 30764827: Refaat et al. 2019; 30650640: Abdallah et al. 2019; 29415625: Laenens et al. 2019). Homozygous LAMA4 knockout mice show microvascular anomalies and develop cardiomyopathy, neurological dysfunction, and kidney disease, while heterozygous mice do not show a phenotype (11809810: Thyboll et al. 2002; 11369940: Patton et al. 2001; 15814800: Wallquist et al. 2005; 16204254: Wang et al. 2006; 20035058: Abrass et al. 2010). Approximately one-third of zebrafish treated with morpholinos against LAMA4 show cardiovascular dysfunction and hemorrhage, but fish injected with a lower dose show no phenotype (17646580: Knöll et al. 2007). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

16204254 11809810 17646580 26406308 20035058