Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy

Santos Martín, José LuisMiranda, José PatricioLagos, Carlos F.Cortés, Víctor A.2025-04-112025-04-112024-11-28Santos, J. L., Miranda, J. P., Lagos, C. F., Cortés, V. A. (2024) Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy. Frontiers in Genetics, 15, 1-12. https://doi.org/10.3389/FGENE.2024.1468878.1664-802110.3389/FGENE.2024.1468878https://academica-e.unavarra.es/handle/2454/53950Introduction: 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.application/pdfeng© 2024 Santos, Miranda, Lagos and Cortés. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).LipodystrophyLMNADe novoExomePathogenic mutationCase Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophyinfo:eu-repo/semantics/article2025-04-11info:eu-repo/semantics/openAccess