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

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dc.catalogadoraba
dc.contributor.authorSantos Martín, José Luis
dc.contributor.authorMiranda Marín, José Patricio
dc.contributor.authorLagos, Carlos F.
dc.contributor.authorCortés Mora, Víctor Antonio
dc.date.accessioned2025-09-09T21:33:56Z
dc.date.available2025-09-09T21:33:56Z
dc.date.issued2024
dc.description.abstractIntroduction 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.
dc.description.funderFONDECYT; Folios: 1221146, Anillo ACT210039
dc.description.funderFondequip; Folio: EQM230130
dc.description.funderFONDECYT; Folio: 1150416
dc.description.funderCentro Basal Ciencia and Vida; Folio: FB210008/ANID
dc.description.funderNLHPC (CCSS210001)
dc.fechaingreso.objetodigital2025-09-09
dc.format.extent10 páginas
dc.fuente.origenSCOPUS
dc.fuente.origenWOS
dc.identifier.doi10.3389/fgene.2024.1468878
dc.identifier.eissn1664-8021
dc.identifier.scopusidSCOPUS_ID:85211640027
dc.identifier.urihttps://doi.org/10.3389/fgene.2024.1468878
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/105646
dc.identifier.wosidWOS:001374825800001
dc.information.autorucEscuela de Medicina; Santos Martín, José Luis; 0000-0003-2895-0369; 1005923
dc.information.autorucEscuela de Medicina; Miranda Marín, José Patricio; 0000-0002-8270-1112; 1126717
dc.information.autorucEscuela de Medicina; Cortés Mora, Víctor Antonio; 0000-0002-1658-0965; 7576
dc.language.isoen
dc.nota.accesocontenido completo
dc.publisherFRONTIERS MEDIA SA
dc.revistaFRONTIERS IN GENETICS
dc.rightsacceso abierto
dc.rights.licenseAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectLipodystrophy
dc.subjectLMNA
dc.subjectDe novo
dc.subjectExome
dc.subjectPathogenic mutation
dc.subject.ddc610
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleCase Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy
dc.typeartículo
dc.volumen15
sipa.codpersvinculados1005923
sipa.codpersvinculados1126717
sipa.codpersvinculados7576
sipa.trazabilidadSCOPUS;2024-12-22
sipa.trazabilidadWOS;2024-12-28
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