SUN-593 Variants in Known Monogenic Causal Genes of Hypertriglyceridemia Are Not Major Contributors for Hypertriglyceridemia in Lipodystrophy Due to a LMNA Mutation

Background: Lipodystrophy is a heterogeneous disorder of adiposity, and one common lipid manifestation is hypertriglyceridemia (HTG). The LMNA gene, which encodes for nuclear envelope proteins, is a known causal gene for heritable lipodystrophy. At present, underlying mechanisms for each clinical manifestation of lipodystrophy due to a LMNA mutation are unknown. Hypothesis: A likely explanation for HTG in lipodystrophy is the paucity of adipose tissue where excess triglycerides (TGs) are normally stored, thus it may not be due to a specific defect in lipoprotein metabolism. Consequently, rare variants in HTG-associated genes would not be expected to be major contributors for HTG in lipodystrophy with LMNA mutations. Method: A proband and her father with a clinical diagnosis of lipodystrophy were recruited into an IRB-approved study investigating molecular etiologies of dyslipidemia at the University of Pennsylvania. Next-generation sequencing (NGS) with the LipidSeq panel, targeting causal genes for lipodystrophy, and monogenic HTG was performed, and confirmed by Sanger sequencing. Also, unweighted TG-polygenic scores by summing the number of TG-raising alleles from 14 single nucleotide polymorphisms (SNPs) associated with TG levels were assessed. Results: The proband and her father were diagnosed with lipodystrophy of two different subtypes, generalized in the daughter and partial in the father. The proband reported a gradual loss of subcutaneous fat starting around age 10. A highest reported TG in the proband was19,000 mg/dL with eruptive xanthomas, whereas TG in the father was never >500 mg/dL. Their BMI’s and DEXA body fat% were 12.9 kg/m(2) and 7% in the proband, and 25.7 kg/m(2) and 25% in the father, corresponding to their fat storage capacities. The molecular analyses revealed only a lipodystrophy causal mutation in LMNA, c.29C>T, T10I with no other significant findings in18 other lipodystrophy-related genes. No deletion or duplication was identified by a targeted array CGH of LMNA. As predicted, no rare monogenic variants in HTG-causal genes (LPL, GPIHBP1, APOA5, APOC2, LMF1, GPD1) were identified in either subject. However, TG-polygenic scores were 17/28 (95(th) %ile) in the proband, and 13/28 (50(th) %ile) in the father, the same trend as the level of HTG levels seen in them. Apolipoprotein E genotypes were non-contributory, (3/3) in the proband, and (3/4) in the father. Conclusion: Our findings support that the pathophysiology of HTG in lipodystrophy is likely to be due to lack of TG-storage space (adipose tissues), and is unlikely due to a defect in lipoprotein metabolism seen in patients with rare monogenic HTG-variants. Although the HTG-polygenic score was higher in the proband, and the accumulative effects of the at-risk alleles may be contributor to the HTG phenotype, it is unlikely to be the leading cause of severe HTG seen in the proband.