Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Dec 18;111(1):e214-e224.
doi: 10.1210/clinem/dgaf279.

Novel and Ultrarare Heterozygous Missense LMNA Variants Causing Familial Partial Lipodystrophy

Anum  1 , Xilong Li  2 , Abhimanyu Garg  1
Affiliations

Novel and Ultrarare Heterozygous Missense LMNA Variants Causing Familial Partial Lipodystrophy

Anum et al. J Clin Endocrinol Metab. .

Abstract

Context: Familial partial lipodystrophy, type 2 (FPLD2) or the Dunnigan variety, is a rare, autosomal dominant disorder characterized by selective loss of subcutaneous fat from the extremities and is caused by over 50 heterozygous missense LMNA variants. However, some patients with FPLD2 do not harbor the known pathogenic LMNA variants and there are only limited genotype-phenotype segregation data for a few other variants.

Objective: To report the genotype-phenotype relationships in 4 families with ultrarare and novel LMNA variants causing FPLD2.

Methods: Clinical, anthropometric, and laboratory data of affected and unaffected subjects from 4 families with female probands presenting with FPLD2 phenotype were collected retrospectively. The main parameters were clinical phenotype, skinfold thickness, regional body fat by dual-energy X-ray absorptiometry (DXA), metabolic variables, and prevalence of diabetes mellitus and hypertriglyceridemia.

Results: We found 2 ultrarare (p.N466D, and p.K515E) and 2 novel (p.R582S, and p.L241P) LMNA heterozygous variants in 4 unrelated FPLD2 families. All adult affected females had thigh skinfold thickness below the 10th percentile of normal and lower extremity fat below the 1st percentile of normal suggesting "typical" FPLD2. None of our patients had any cardiomyopathy, muscular dystrophy, neuropathy, or any progeroid features.

Conclusion: Our data provide further supporting evidence for the pathogenicity of 2 previously reported ultrarare heterozygous LMNA variants, p.N466D and p.K515E. We also report 2 novel variants, p.R582S and p.L241P, in patients with FPLD2. Thus, our study broadens the spectrum of pathogenic/likely pathogenic LMNA variants in FPLD2.

Keywords: LMNA variant; Dunnigan variety; FPLD2; familial partial lipodystrophy; lamin A/C.

PubMed Disclaimer

References

    1. Peters JM, Barnes R, Bennett L, Gitomer WM, Bowcock AM, Garg A. Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21-22. Nat Genet. 1998;18(3):292‐295. - PubMed
    1. Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000;9(1):109‐112. - PubMed
    1. Besci O, de Freitas MC F, Guidorizzi NR, et al. Deciphering the clinical presentations in LMNA-related lipodystrophy: report of 115 cases and a systematic review. J Clin Endocrinol Metab. 2024;109(3):e1204‐e1224. - PMC - PubMed
    1. Garg A, Vinaitheerthan M, Weatherall PT, Bowcock AM. Phenotypic heterogeneity in patients with familial partial lipodystrophy (dunnigan variety) related to the site of missense mutations in lamin a/c gene. J Clin Endocrinol Metab. 2001;86(1):59‐65. - PubMed
    1. Garg A, Speckman RA, Bowcock AM. Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene. Am J Med. 2002;112(7):549‐555. - PubMed

LinkOut - more resources