Novel and Ultra-Rare Heterozygous Mis-sense LMNA variants causing Familial Partial Lipodystrophy

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 FPLD2 patient 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 four families with ultra rare and novel LMNA variants causing FPLD2.

Methods: Clinical, anthropometric and laboratory data of affected and unaffected subjects from four 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 two ultra-rare (p.N466D, and p.K515E) and two 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.

Conclusions: Our data provide further supporting evidence for the pathogenicity of two previously reported ultra-rare heterozygous LMNA variants, p.N466D, and p.K515E. We also report two 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.