SAT-574 Whole Exome Sequencing Identifies Several Variants Associated with Immune Deficiency, Inflammasomopathy and Non-Ischemic Dilated Cardiomyopathy in a Complex Case of Acquired Generalized Lipodystrophy
Authors: Brandao Marjorie Azevedo Jales , de Freitas Maria Cristina Foss , Akinci Baris , Hannibal Mark , Walkovich Kelly , Oral Elif A 
Published: May 2020

Background: Acquired generalized lipodystrophy (AGL) is characterized by near-total fat loss that develops after birth. Although the molecular pathogenesis of AGL is unclear, there is a link to autoimmunity and inflammation. Notably, the panniculitis associated variety of AGL may present with subcutaneous inflammatory nodules that ultimately progress to generalized fat loss. Here, we report on a complex patient with AGL in whom whole-exome sequencing (WES) identified several pathogenic variants and variants of uncertain significance (VUS) that encourage us to think about AGL more broadly. Clinical Case: This is a 38-year-old male who was first diagnosed with juvenile rheumatoid arthritis at age 2, after being evaluated for delayed ability to ambulate. At that time, he was also diagnosed with Weber-Christian disease following a skin biopsy due to the suspicion of panniculitis. Over time, he progressively lost body fat throughout the body and developed hypertriglyceridemia, hypertension, and nephropathy leading to the diagnosis of AGL. At age 10, he was diagnosed with type 1 diabetes mellitus, and at age 14, with autoimmune hepatitis. Due to the tightening of his hands, calf pain, and increased CPK levels, a muscle biopsy was performed, suggesting polymyositis. He had been treated with azathioprine and steroids, which were discontinued at age 26, after a liver biopsy that showed grade 2 fibrosis. Further, he was diagnosed with non-ischemic dilated cardiomyopathy (DCM), evolving with atrial fibrillation with a rapid ventricular response and complicated with left atrial appendage thrombus. Of interest, his mother and two maternal aunts had been diagnosed with atrial fibrillation. One of his maternal uncles presented non-ischemic cardiomyopathy and an early sudden cardiac arrest. His mother also had mitochondrial myopathy, and his father had type 2 diabetes mellitus and IgG deficiency. WES identified three different variants: a maternally inherited pathogenic variant in TTN (c.88473_88477delAGCTT; p.W29493X) associated with DCM, a paternally inherited pathogenic variant in TNFRSF13B (c.310T&gt;C; p.C104R) associated with CVID/IgA deficiency, and a maternally inherited variant of uncertain clinical significance in NLRP3 (c.1469G&gt;A; p.R490K). Although the frequency of this variant was relatively high, several variants in the NLRP3 gene have been previously associated with inflammasomopathy. Conclusion: This case highlights challenging presentations of AGL and the complexity of the disease. As we are yet beginning to understand the molecular mechanisms behind the so-called “acquired fat loss” and its relation to inflammatory and complex immune system diseases, further efforts are critical to better recognize different AGL phenotypes and phenotype-genotype correlations. Additional efforts should be placed on WES for AGL patients and functional validation of identified VUSs.