Partial Lipodystrophy and LMNA p.R545H Variant

Area of Science:

• Genetics
• Molecular Biology
• Medical Science

Background:

• Laminopathies arise from mutations in the LMNA gene, leading to diverse clinical presentations.
• The precise mechanisms driving tissue specificity and varied clinical outcomes in laminopathies remain unclear.

Purpose of the Study:

• To investigate the clinical and molecular characteristics of a patient with a heterozygous LMNA c.1634G>A (p.R545H) variant.
• To explore the variable expressivity and incomplete penetrance associated with the LMNA p.R545H variant.

Main Methods:

• Case study of a patient with suspected lipodystrophy and a heterozygous LMNA p.R545H variant.
• In silico analysis of the p.R545H amino acid substitution.
• Review of clinical data from other patients with the LMNA p.R545H allele.

Main Results:

• The patient presented with mild, transient myopathy and abnormal subcutaneous fat distribution, mimicking familial partial lipodystrophy type 2.
• The LMNA p.R545H variant, found at low frequency, is predicted to be damaging by in silico analysis.
• Other patients with the p.R545H allele exhibited significant heterogeneity in body fat distribution and organ involvement.

Conclusions:

• The heterozygous LMNA p.R545H variant displays incomplete penetrance and highly variable expressivity.
• Additional genetic, epigenetic, or environmental factors likely contribute to the phenotypic variability observed in patients with this variant.