Submission Details

The relationship between the ABHD5 gene and Chanarin-Dorfman syndrome (CDS), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 23, 2022. ABHD5 encodes abhydrolase domain-containing protein 5, lysophosphatidic acid acyltransferase, an acyltransferase that is involved in the synthesis of phosphatidic acid via acylating lysophosphatidic acid to phosphatidic acid, the major intermediate in membrane and storage lipid biosynthesis, and also functions as a coactivator of adipocyte triglyceride lipase to help regulate triacylglycerol homeostasis in adipocytes (PMID: 18606822). Individuals with CDS show impaired ABHD5-mediated lipolysis, reflecting impaired ABHD5 activation of PNPLA2 (PMID: 16679289), resulting in the characteric disease manifestation of triacylglycerol accumulation in multiple tissues (as reviewed in PMID: 33455044).

The disease mechanism of CDS is loss of function. CDS was first reported in 1966 by Rosenszajin (PMID: 5330405), and the first report of biallelic variants in ABHD5 among CDS patients was in 2001 by Lefevre (PMID: 11590543). Both case-level (genetic) and experimental evidence support the relationship between ABHD5 and CDS. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 11590543; PMID: 18339307; PMID: 25682902; PMID: 21122093). In total, nine variants from eight probands in four 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 ABHD5 and CDS includes: the biochemical function of the gene product (abhydrolase domain-containing protein 5, lysophosphatidic acid acyltransferase) being consistent with the clinical and biochemical findings identified individuals with CDS (as reviewed in PMID: 33455044, PMID: 19061969); the protein-protein interaction between ABHD5 and adipose triglyceride lipase (encoded by the PNPLA2 gene) (PMID: 16679289), which has been curated by the LD GCEP as Definitively associated with Neutral lipid storage disease with myopathy; functional alteration (impaired lipolysis in COS-7 cells transfected with variants of ABHD5 in which key binding pocket amino acid residues were altered (PMID: 35173175); the biochemical and clinical features of ABHD5 knockout animal models (PMID: 20023287: knockout mouse model; PMID: 25202121: knockout C. elegans model); and rescue of CDS patient fibroblasts (harboring a loss of function ABHD5 variant) via infection with an adenovirus harboring wild-type ABHD5 (PMID: 16679289). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, ABHD5 is definitively associated with CDS. 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 August 2, 2022 (SOP v9).