Submission Details

The LAMP2 gene is associated with Danon disease, an X-linked disorder characterized by vacuolar cardiomyopathy, and to a lesser extent skeletal myopathy, cognitive defects and retinopathy (reviewed in Rowland et al., 2016 PMID: 27165304). As an X-linked disorder males are predominantly affected but heterozygous female carriers have been shown to develop cardiomyopathy, albeit with abated progression compared to affected males (Boucek et al., 2011 PMID: 21415759). The majority of mutations are LOF (frameshift and non-sense) but missense, splice site, and large copy number variants (CNVs), both duplications and deletions, have been reported, as well as de novo mutations. LAMP2 has three different splice isoforms (LAMP-2A, LAMP-2B, LAMP-2C) due to alternative splicing in exon 9 (terminal exon). The LAMP-2B isoform is the most widely implicated in Danon Disease, as it is found to be most abundantly expressed in the heart, skeletal muscle and brain (Konecki et al., 1995 PMID: 7488019), but does not negate the other isoforms as having a role in disease. LAMP2 is the lysosomal-associated membrane protein 2 and functions as a receptor to mediate lysosomal associated degradation or proteins, or autophagy (reviewed in D’Souza et al., 2014, PMID: 25228319). Multiple cases are reported in the literature but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is disrupted autophagy that results in aberrant vacuole accumulation in cells. This gene-disease association is supported by the function of the gene product, alteration in normal function in non-patient cells, and animal models. In summary, LAMP2 is definitively associated with Danon disease. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Data on the occurrence of cardiomyopathy in individuals with Danon disease was collected by the Hypertrophic Cardiomyopathy Gene Curation Committee (subgroup of the Cardiovascular Working Group). Mutation of LAMP2 results in the development of hypertrophic cardiomyopathy (in 88% of cases of Danon disease) that rapidly progresses to dilated cardiomyopathy (reviewed in Rowland et al., 2016 PMID: 27165304). The progression of cardiomyopathy is caused by aberrant accumulation of autophagic vacuoles in the heart and skeletal muscle. The progressive nature of LAMP2-associated cardiomyopathy requires heart transplantation by the third decade in order to avoid death (reviewed in D’Souza et al., 2014, PMID: 25228319).