Heterozygous pathogenic PPARG variants in patients with severe hypertriglyceridemia

Heterozygous pathogenic variants in PPARG cause familial partial lipodystrophy type 3 (FPLD3, Mendelian Inheritance in Man [MIM] #604367), a heritable form of insulin resistance with multiple metabolic disturbances including hypertriglyceridemia. We investigated the prevalence of FPLD3 individuals in our cohort of patients with multifactorial chylomicronemia syndrome (MCS). We used our targeted DNA sequencing panel to screen the PPARG gene in 182 clinically diagnosed MCS patients. We found that 3.3% of MCS patients (6/182) had a heterozygous pathogenic PPARG variant, consistent with a diagnosis of FPLD3. The variants were PPARG p.Lys186fs (ClinVar identifier 8132), p.Glu217Lys, p.Pro454fs (ClinVar identifier 436405), p.Met284Ile, p.Ser383Arg, and p.Arg181Trp. None of these patients had previously been diagnosed with FPLD3 and their clinical and biochemical features were otherwise comparable to those of the entire MCS cohort. A small but clinically relevant subgroup of individuals with MCS has FPLD3. Clinical features in FPLD3 are subtle but the phenotype can be metabolically severe. Genetic screening of patients with severe hypertriglyceridemia should include assessment of lipodystrophy genes, since management of lipodystrophy patients is distinct from that of typical MCS patients.