The relationship between the PNPLA2 gene and neutral lipid storage disease with myopathy (NLSDM), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 9, 2022. PNPLA2 encodes patatin-like phospholipase domain-containing protein (aka adipose triglyceride lipase), an enzyme involved in triglyceride hydrolysis in adipocytes and in non-adipocyte droplets (PMID: 15550674) via catalyzing the hydrolysis of long-chain fatty acid esters at the sn2 position of the glycerol backbone. Among individuals with NLSDM, PNPLA2 deficiency leads to accumulation of incompletely degraded triglycerides in leukocytes and skeletal and cardiac muscle cells, resulting in the characteristic disease manifestations of myopathy and cardiomyopathy (PMID: 17187067, PMID: 21544567).
The disease mechanism of NLSDM is loss of function. NLSDM was first reported in 2007 (PMID: 17187067), and this publication was the first report of biallelic variants in PNPLA2 among patients with NLSDM. Both case-level (genetic) and experimental evidence support the relationship between PNPLA2 and NLSDM. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 17187067, PMID: 21544567, PMID: 25956450, PMID: 24332944, PMID: 22832386). In total, 10 variants from eight probands in five publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached.
Experimental evidence for the relationship between PNPLA2 and NLSDM includes the biochemical function of the gene product (patatin-like phospholipase domain-containing protein, aka adipose triglyceride lipase) being consistent with the clinical and biochemical findings identified individuals with NLSDM (PMID: 17187067, PMID: 21544567), the biochemical and clinical features of a PNPLA2 knockout mouse animal (PMID: 16675698), and rescue of a PNPLA2 knockout mouse model via reexpression of a wild-type PNPLA2 transgene (PMID: 21857651). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, PNPLA2 is definitively associated with NLSDM. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on July 21, 2022 (SOP v9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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