Submission Details

Human pathogenic PPARG variants were first reported in autosomal dominantly inherited severe insulin resistance in 1999 (Barroso et al, PMID:10622252), attributed to lipodystrophy shortly afterwards (Agarwal et al, PMID: 11788685). We have now curated the inheritance pattern for PPARG-related lipodystrophy as semidominant because, while most cases are autosomal dominant, very rarely a recessive mode of inheritance has been reported (Dyment et al, PMID:24980513; Gosseaume et al, PMID:36806620).

Both loss of function and dominant negative variants have been reported. Typical autosomal dominant cases due to heterozygous variants present with loss of subcutaneous adipose tissue, especially of the limbs, and metabolic complications, in a form of familial partial lipodystrophy (Chen et al et al, PMID:35422762; PMID:36806620; Vasandani et al, PMID:36397776). The occasional recessive cases typically feature early-onset, congenital generalized lipodystrophy, also known as Berardinelli-Seip syndrome, due to biallelic variants in PPARG (PMIDs:24980513, 36806620).

At least 60 lipodystrophy-causing PPARG variants (primarily missense) 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 have been reported in at least 35 probands in 14 publications (PMIDs: 17766367, 24980513, 16965332, 10622252, 17299075, 29622583, 35422762, 17011503, 12453919, 11788685, 22750678, 34168618, 36806620, 36397776), with most cases presenting as familial partial lipodystrophy and two cases with 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), expression studies and functional alterations. Total points for the experimental evidence are 4. Total points for genetic and experimental evidence together are thus 16.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found both differences in inheritance pattern and phenotypic variability, but also overlap in the implicated variants. Specifically, PPARG has two associated diseases, namely the more commonly associated autosomal dominant familial partial lipodystrophy (OMIM:604367), and the more rarely associated autosomal recessive congenital, generalized lipodystrophy. Because the latter is rare and there is overlap in the implicated variants, these two entities have been lumped in a single curation of lipodystrophy (MONDO: 0006573).

In summary, PPARG is definitively associated with semidominant lipodystrophy, with most cases presenting as autosomal dominant familial partial lipodystrophy in adolescents and young adults. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.