Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy
IntroductionInherited 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 patho...
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Frontiers Media S.A.
2024-11-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2024.1468878/full |
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| author | José L. Santos José L. Santos José Patricio Miranda José Patricio Miranda Carlos F. Lagos Carlos F. Lagos Víctor A. Cortés |
| author_facet | José L. Santos José L. Santos José Patricio Miranda José Patricio Miranda Carlos F. Lagos Carlos F. Lagos Víctor A. Cortés |
| author_sort | José L. Santos |
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| description | IntroductionInherited 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.MethodsA 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).ResultsThe 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.ConclusionIn 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. |
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| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj-art-d5d8c689fe0b46e392e39f5984b87b082024-11-28T06:33:37ZengFrontiers Media S.A.Frontiers in Genetics1664-80212024-11-011510.3389/fgene.2024.14688781468878Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophyJosé L. Santos0José L. Santos1José Patricio Miranda2José Patricio Miranda3Carlos F. Lagos4Carlos F. Lagos5Víctor A. Cortés6Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, ChileDepartment of Health Sciences, Institute for Sustainability and Food Chain Innovation (IS-FOOD), Public University of Navarre, Pamplona, SpainDepartment of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, ChileBupa Lab, Part of Bupa Chile, Santiago, ChileChemical Biology and Drug Discovery Laboratory, Escuela de Química y Farmacia, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, ChileCentro Ciencia and Vida, Fundación Ciencia and Vida, Santiago, ChileDepartment of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, ChileIntroductionInherited 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.MethodsA 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).ResultsThe 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.ConclusionIn 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.https://www.frontiersin.org/articles/10.3389/fgene.2024.1468878/fulllipodystrophyLMNAde novoexomepathogenic mutation |
| spellingShingle | José L. Santos José L. Santos José Patricio Miranda José Patricio Miranda Carlos F. Lagos Carlos F. Lagos Víctor A. Cortés Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy Frontiers in Genetics lipodystrophy LMNA de novo exome pathogenic mutation |
| title | Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy |
| title_full | Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy |
| title_fullStr | Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy |
| title_full_unstemmed | Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy |
| title_short | Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy |
| title_sort | case report concurrent de novo pathogenic variants in the lmna gene as a cause of sporadic partial lipodystrophy |
| topic | lipodystrophy LMNA de novo exome pathogenic mutation |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2024.1468878/full |
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