Human pathogenic AGPAT2 variants were first reported in 2002 in association with autosomal recessive congenital generalized lipodystrophy (Agarwal et al, PMID:11967537). We have curated the inheritance pattern for AGPAT2 - related lipodystrophy as autosomal recessive because a recessive mode of inheritance has been consistently reported since 2002 (Agarwal et al, PMIDs:12765973; 11967537; Gorin et al, PMID:32412105).
Homozygous or compound heterozygous variants, including nonsense, splice site, frameshift variants and small deletions have been reported. Typical autosomal recessive cases due to homozygous or compound heterozygous variants presented with hypertriglyceridemia, hepatic steatosis, hyperinsulinemia, pancreatitis and diabetes mellitus features even in early childhood and adolescence (Magre et al, PMID: 12765973; Gorin et al et al, PMID:32412105; Abuzenadah et al, PMID:38231342).
At least 50 lipodystrophy-causing AGPAT2 variants (primarily nonsense or frameshift) have been reported in humans. Evidence supporting the association of this gene with lipodystrophy includes case-level data, segregation data, and experimental data. The aggregated score for case-level and segregation data is 12 points. Variants in this gene were curated for this summary in 12 probands in 8 publications (PMIDs: 38231342,35474974, 32153340, 32412105, 32280377, 23430550, 22902344,12765973), with cases presenting as congenital, generalized lipodystrophy. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached; this has not been curated exhaustively. This gene-disease relationship is supported by functional assays (both individual and massively parallel), knockout mouse models, expression studies and functional alterations (PMIDs: 21051554, 38127985, 27408775, 37752957, 38623324). Total points for the experimental evidence are 5. Total points for genetic and experimental evidence together are 17.
Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in inheritance pattern and phenotypic variability. Therefore, we curated AGPAT2 as associated with autosomal recessive congenital, generalized lipodystrophy (OMIM: 608594) and have been lumped in a single gene curation of lipodystrophy (MONDO: 0006573).
In summary, AGPAT2 is definitively associated with autosomal recessive, congenital generalized lipodystrophy from birth or early infancy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
This classification was approved by the ClinGen Monogenic Diabetes GCEP on November 13, 2024 (SOP Version 11).
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