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

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.

Lipedema: Insights into Morphology, Pathophysiology, and Challenges

“…A next-generation sequencing (NGS) panel comprising 305 genes strongly linked to lipedema and/or overlapping diseases relevant to lipedema has been developed. Genome sequencing of 162 Italian and American patients with lipedema was performed, and 21 heterozygous detrimental variants were detected, according to 3 out of 5 predictors, including perilipin 1 (PLIN1), lipase E (LIPE), aldehyde dehydrogenase 18 family member A1 (ALDH18A1), PPARG, growth hormone receptor (GHR), INSR, ryanodine receptor 1 (RYR1), Niemann–pick C intracellular cholesterol transporter 1 (NPC1), proopiomelanocortin (POMC), nuclear receptor subfamily 0 group B member 2 (NR0B2), glucokinase regulator (GCKR), and peroxisome proliferator-activated receptor alpha (PPARA) in 17 patients [ 134 ]. Variations of the above-listed genes (except for GHR and ALDH18A1) have been linked to several fat disorders.…”

“…Variations of the above-listed genes (except for GHR and ALDH18A1) have been linked to several fat disorders. Meanwhile, variants in ALDH18A1 have been linked to connective tissue disorders known as cutis laxa, wherein overhangs of skin folds are observed due to a decrease in elastic tissue formation, similar to the hypermobile joints observed in lipedema [ 134 ]. Mutations of GHR have been linked to partial GH deficiency and short stature, which have been confirmed in a single familial case of lipedema [ 126 ].…”

“…Mutations of GHR have been linked to partial GH deficiency and short stature, which have been confirmed in a single familial case of lipedema [ 126 ]. A common trend in these variants is their involvement in steroid biosynthesis, lipid metabolism, and insulin signaling [ 134 ]. Knowing genetic variants or polymorphisms associated with genes of interest in lipedema through NGS will aid concurrent analyses of multiple genes in large cohorts of patients, helping develop diagnostic parameters/therapeutic options for lipedema.…”

Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis

“…Gene-sequencing studies are underway in multiple centers specializing in lymphedema to identify potential variations in lipedema. Notably, next-generation sequencing has elucidated 21 deletion variants in 12 genes shared by a subset of patients with lipedema; these genes were associated with adipogenesis, adipocyte biology, and metabolism consistent with aberrant adipose tissue remodeling and function and with the heterogenous nature of lipedema [ 140 ]. Similarly, a recent genome-wide association study of 130 lipedema patients identified several single nucleotide polymorphisms, and the authors highlighted those associated with lipoma formation and hormone synthesis as mechanistically relevant [ 141 ].…”

Next-Generation Sequencing of a Large Gene Panel for Outcome Prediction of Bariatric Surgery in Patients with Severe Obesity

“…Genetically, obesity can be classified as: monogenic, primarily caused by mutations in several genes involved in the leptin/melanocortin and adipogenesis pathways (such as MC4R, LEP, LEPR, POMC and PCSK1) [20][21][22]; syndromic, associated with neurodevelopmental abnormalities and/or other malformations due to chromosomal abnormalities or single nucleotide variations affecting genes that encode pivotal proteins in the regulation of energy balance [23]; polygenic, caused by the contribution of more than one genetic variant, whose effect is amplified in a 'weight-gain-promoting' environment [24]. In the last ten years, next-generation sequencing (NGS) approaches have greatly improved the rate of molecular diagnosis because of their extremely high specificity, sensitivity, accuracy, and their timeand cost-effectiveness [20,[25][26][27][28][29][30]. To date, about 250 genetic variants associated with BMI or waist-to-hip ratio have been identified through genome-wide association studies and whole genome or exome sequencing [31].…”