Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy
Year: 2024
Type: article
Study design: Case Report
Abstract: Introduction Inherited lipodystrophies are a group of rare diseases defined by severe reduction in adipose tissue mass and classified as generalized or partial. We report a non-familial (sporadic) case of partial lipodystrophy caused by a novel genetic mechanism involving closely linked de novo pathogenic variants in the LMNA gene. Methods A female adult with partial lipodystrophy and her parents were evaluated for gene variants across the exome under different mendelian inheritance models (autosomal dominant, recessive, compound heterozygous, and X-linked) to find pathogenic variants. Body composition was assessed via dual-energy X-ray absorptiometry (DXA). Results The patient showed absence of adipose tissue in the limbs; preservation of adiposity in the face, neck, and trunk; muscular hypertrophy, hypertriglyceridemia and insulin resistance. DXA revealed a fat mass of 15.4%, with android-to-gynoid ratio, trunk/limb, and trunk/leg ratios exceeding the published upper limits of 90% reference intervals. Two heterozygous missense de novo pathogenic variants in cis within the LMNA gene were found in the proband: p.Y481H and p.K486N (NP_733821.1). These variants have functional effects and were reported in inherited Emery-Dreifuss muscular dystrophy 2 (p.Y481H) and familial partial lipodystrophy type 2 (p.K486N). Molecular modeling analyses provided additional insights into the protein instability conferred by these variants in the lamin A/C Ig-like domain. Conclusion In a case of sporadic partial lipodystrophy, we describe two concurrent de novo pathogenic variants within the same gene (LMNA) as a novel pathogenic mechanism. This finding expands the genetic and phenotypic spectrum of partial lipodystrophy and laminopathy syndromes.
Source: Frontiers in Genetics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,295
Awards: ASSOCIATION BETWEEN GENE VARIANTS OF THE MITOCHONDRIAL GENOME AND PROTEOME WITH INSULIN SECRETION/SENSITIVITY INDEXES AND GLYCEMIC-RELATED TRAITS, LABORATORIO NACIONAL DE SUPERCOMPUTACION, G4193446334, INTERORGANELLE LIPID DROPLET-TO-MITOCHONDRIA CONTACTING IN LIPODYSTROPHY AND FATTY LIVER DISEASE, G5350179487, G5653102473, G5776878938, G6372545043, FENOTIPIFICACION METABOLICA DE ANIMALES PEQUENOS UNA HERRAMIENTA NECESARIA PARA LA INVESTIGACION BIOMEDICA DE PUNTA EN OBESIDAD DIABETES Y METABOLISMO, NEUROENDOCRINE REGULATION OF FOOD INTAKE AND ENERGY EXPENDITURE AN INTEGRATED VIEW OF OBESITY AND LIPODYSTROPHY, CENTRO CIENTIFICO TECNOLOGICO DE EXCELENCIA CIENCIA & VIDA (CIENCIA & VIDA)
OpenAlex ID: W4404832744