Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by the selective loss of adipose tissue. Its estimated prevalence is as low as 1 in 1 million. The deficiency of metabolically active adipose tissue is closely linked with a wide range of metabolic complications, such as insulin resistance, lipoatrophic diabetes, dyslipidemia with severe hypertriglyceridemia, hypertension or hepatic steatosis. Moreover, female patients often develop hyperandrogenism, hirsutism, polycystic ovaries and infertility. The two most common types are FPLD type 2 and 3. Variants within LMNA and PPARG genes account for more than 50% of all reported FPLD cases. Because of its high heterogeneity and rarity, lipodystrophy can be easily unrecognized or misdiagnosed. To determine the genetic background of FPLD in a symptomatic woman and her close family, an NGS custom panel was used to sequence LMNA and PPARG genes. The affected patient presented fat deposits in the face, neck and trunk, with fat loss combined with muscular hypertrophy in the lower extremities and hirsutism, all features first manifesting at puberty. Her clinical presentation included metabolic disturbances, including hypercholesterolemia with severe hypertriglyceridemia, diabetes mellitus and hepatic steatosis. This together with her typical fat distribution and physical features raised a suspicion of FPLD. NGS analysis revealed the presence of missense heterozygous variant c.443G>A in exon 4 of PPARG gene, causing glycine to glutamic acid substitution at amino acid position 148, p.(Gly148Glu). The variant was also found in the patient’s mother and son. The variant was not previously reported in any public database. Based on computational analysis, crucial variant localization within DNA-binding domain of PPARγ, available literature data and the variant cosegregation in the patient’s family, novel c.443G>A variant was suspected to be causative. Functional testing is needed to confirm the pathogenicity of the novel variant. Inherited lipodystrophy syndromes represent a heterogenous group of metabolic disorders, whose background often remains unclear. A better understating of the genetic basis would allow earlier diagnosis and targeted treatment implementation.
Keywords: PPARG gene; familial partial lipodystrophy type 3; genetic background; genotype-phenotype correlation; inherited lipodystrophy; lipids; metabolic disorder.