Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to a Pathogenic LMNA Variant R482: Maternal Transmission to Non-Identical Twins

Paola Andrea Duque-Cordoba,1,2 Lorena Diaz-Ordoñez,1,2 Laura Carvajal-del-Castillo,2,3 Daniela Marmolejo,4 Andres Felipe Leal,5– 7 Harry Pachajoa1– 3,5 1Genomic Medicine Laboratory, Universidad Icesi, Cali, Colombia; 2Faculty of Health Sciences, Universidad Icesi, Cali, Colombia; 3Genetics Service, Fundación Valle del Lili, Cali, Colombia; 4Medic IPS, Tuluá, Colombia; 5Clinical Research Center, Fundación Valle de Lili, Cali, Colombia; 6Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá, Colombia; 7International Institute of Molecular and Cell Biology, Warsaw, PolandCorrespondence: Harry Pachajoa, Faculty of Health Sciences, Universidad Icesi, Calle 18 No. 122 - 135, Pance, Cali, Colombia, Email [email protected]: Familial partial lipodystrophy type 2 (FPLD2), or Dunnigan syndrome, is a rare autosomal dominant disorder caused by mutations in the lamin A (LMNA) gene, most frequently involving the p.R482W variant. It is characterized by regional loss of subcutaneous fat and severe metabolic abnormalities, particularly dyslipidemia, insulin resistance, and hepatic steatosis. We report a family with three individuals -mother and two siblings- carrying the same pathogenic LMNA c.1444C>T (p.R482W) variant but exhibiting distinct clinical and biochemical profiles. The proband (patient 1) is a 29-year-old male, presented with moderate metabolic disturbances, including hypertriglyceridemia, low levels of high density lipoprotein-cholesterol (HDL-C), and hepatic steatosis, accompanied by physical features such as dorsocervical fat accumulation and winged neck. His dizygotic female twin (patient 2) exhibited a more severe phenotype with triglycerides levels approached 700 mg/dL, insulin resistance, and polycystic ovarian morphology (PCOM). Their 68-year-old mother, also a carrier, showed only mild dyslipidemia and unstable angina. The comparison of dizygotic twins and their mother carrying the same LMNA variant provides a unique opportunity to illustrate how sex, age, and hormonal status modulate metabolic severity in FPLD2. These findings reinforce the clinical relevance of family-based evaluation and early metabolic surveillance, even in mildly affected or asymptomatic carriers.Keywords: lipodystrophy, familial partial, LMNA protein, human, genetic variation, insulin resistance, dyslipidemias