A Multi-Gene Panel to Identify Lipedema-Predisposing Genetic Variants by a Next-Generation Sequencing Strategy.

Sandro Michelini,Valeria Velluti,Barbara Aquilanti,Lucilla Gagliardi,Matteo Bertelli,Giuseppina Matera,Karen L Herbst,Stefano Paolacci,Giacinto Abele Donato Miggiano,Tommaso Beccari,Vincenza Precone,Elisa Sorrentino,Maria Rachele Ceccarini,Elena Manara,Paolo Enrico Maltese,Giuseppe Marceddu,Astrit Dautaj

doi:10.3390/jpm12020268

Abstract

Lipedema is a disabling disease characterized by symmetric enlargement of the lower and/or upper limbs due to deposits of subcutaneous fat, that is easily misdiagnosed. Lipedema can be primary or syndromic, and can be the main feature of phenotypically overlapping disorders. The aim of this study was to design a next-generation sequencing (NGS) panel to help in the diagnosis of lipedema by identifying genes specific for lipedema but also genes for overlapping diseases, and targets for tailored treatments. We developed an NGS gene panel consisting of 305 genes potentially associated with lipedema and putative overlapping diseases relevant to lipedema. The genomes of 162 Italian and American patients with lipedema were sequenced. Twenty-one deleterious variants, according to 3 out of 5 predictors, were detected in PLIN1, LIPE, ALDH18A1, PPARG, GHR, INSR, RYR1, NPC1, POMC, NR0B2, GCKR, PPARA in 17 patients. This extended NGS-based approach has identified a number of gene variants that may be important in the diagnosis of lipedema, that may affect the phenotypic presentation of lipedema or that may cause disorders that could be confused with lipedema. This tool may be important for the diagnosis and treatment of people with pathologic subcutaneous fat tissue accumulation.

Highlights

IntroductionLipedema is characterized by an abnormal and excessive accumulation of subcutaneous fat
The aim of this study was to demonstrate the implementation of an next-generation sequencing (NGS) panel for the diagnosis of non-syndromic lipedema, and evaluate for syndromic forms of lipedema, and to include analysis of candidate genes possibly associated with lipedema, subcutaneous fat tissue accumulation, and fat metabolism that may affect the phenotypic presentation of lipedema
We developed a NGS panel comprising genes that may be important for the differential diagnosis of lipedema, as well as candidate genes to help identify genes involved in the etiopathogenesis of lipedema [2]

Summary

Introduction

Lipedema is characterized by an abnormal and excessive accumulation of subcutaneous fat. It typically affects the lower and/or upper limbs, resulting in a debilitating disease. Lipedema can be considered a component of a spectrum of diseases characterized by dysregulated proliferation of adipose tissue and pain, including Dercum disease, with multiple painful nodules on the trunk and limbs that can be accompanied by lipedema [10,11]; and Madelung disease or multiple symmetric lipomatosis, where nodular fat and lipomas occur on the upper part of the body [3,10,11], but may occur in a distribution similar to lipedema [12]

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