The Journal of clinical endocrinology and metabolism · 2025
Novel and Ultrarare Heterozygous Missense LMNA Variants Causing Familial Partial Lipodystrophy.
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Anum, Li Xilong, Garg Abhimanyu
Аннотация
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.
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.