A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign

Abstract

Background: PPKs represent a heterogeneous group of disorders with hyperkeratosis of palmar and/or plantar skin. PPK, hair shaft abnormalities, cardiomyopathy and arrhythmias can be caused by mutations in desmosomal genes, e.g. desmoplakin (DSP). PPK should trigger genetic testing to reveal mutations with possible related cardiac disease.

Objectives: To report a large multigenerational family with a novel DSP mutation associated with early-onset PPK and adult-onset cardiomyopathy and arrhythmias.

Methods: A custom-designed in-house panel of 35 PPK related genes was used to screen mutations in the index patient with focal PPK. The identified DSP mutation was verified by Sanger sequencing. DNA samples from 20 members of the large multigenerational family were sequenced for the DSP mutation. Medical records were reviewed. Clinical dermatological evaluation was performed, including light microscopy of hair samples. Cardiac evaluation included clinical examination, echocardiography, cardiac magnetic resonance imaging (CMR), electrocardiogram (ECG), Holter monitoring and laboratory tests.

Results: We identified a novel autosomal dominant truncating DSP c.2493delA p.(Glu831Aspfs*33) mutation associated with dilated cardiomyopathy (DCM) with arrhythmia susceptibility and focal PPK as an early cutaneous sign. The mutation was found in nine affected family members, but not in any unaffected members. Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age.

Conclusions: We report a novel truncating DSP mutation causing focal PPK with varying severity and left ventricular dilatation and ventricular extrasystoles. This finding emphasizes the importance of genetic diagnosis in patients with PPK for clinical counselling and management of cardiomyopathies and arrhythmias.

Keywords: dilated cardiomyopathy; genodermatosis; next-generation sequencing; palmoplantar keratoderma.

Figure 1

The family pedigree. The index is marked by an arrow. Genotype: +, heterozygous for DSP c.2493delA p.(Glu831Aspfs*33) mutation; −, wild type allele. Symbols represent the following; right upper quadrant: black for diagnosed DCM or dilated left ventricle, grey for slightly dilated left ventricle or suspected cardiomyopathy; right lower quadrant; black for verified arrhythmias or unexplained elevated TnI concentration, left upper quadrant: black for curly hair, grey for anamnestic reported curly hair that has not been clinically confirmed; left lower quadrant: black for clinically verified PPK, grey for anamnestic reported PPK that has not been clinically confirmed (III:8) or slight hyperkeratosis observed, fitting due to normal friction (III:4). Abbreviations: DCM, dilated cardiomyopathy; TnI, Tropnonin I; PPK, palmoplantar keratoderma.

Figure 2

Dermatological findings in patients with DSP c.2493delA p.(Glu831Aspfs*33) mutation. Variable focal hyperkeratosis of the heels, toes and soles and palmar hyperlinearity (from mild to more prominent) in patients with DSP c.2493delA p.(Glu831Aspfs*33) mutation: (a) index IV:12, (b) III:7, and (c) IV:10.