Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene.
BACKGROUND
Desmin-related myopathy is a clinically heterogenous group of disorders encompassing myopathies, cardiomyopathies, conduction disease, and combinations of these disorders. Mutations in the gene encoding desmin (DES), a major intermediate filament protein, can underlie this phenotype.


OBJECTIVE
The purpose of this study was to investigate the clinical and pathologic characteristics of 27 patients from five families with an identical mutation in the head domain region (p.S13F) of desmin.


RESULTS
All 27 carriers or obligate carriers of a p.S13F DES founder mutation demonstrated a fully penetrant yet variable phenotype. All patients demonstrated cardiac involvement characterized by high-grade AV block at young ages and important right ventricular (RV) involvement. RV predominance was demonstrated by the presence of right bundle branch block in 10 patients (sometimes as a first manifestation) and by RV heart failure in 6 patients, including 2 patients who fulfilled the diagnostic criteria for arrhythmogenic RV cardiomyopathy. Because of this clinical overlap with desmosome cardiomyopathies, we also studied the organization of the intercalated disks, particularly the distribution of desmosomal proteins. Normal amounts of the major desmosomal proteins were found, but the intercalated disks were more convoluted and elongated and had a zigzag appearance.


CONCLUSIONS
In this largest series to date of individuals with a single head domain DES mutation, patients show a variable yet predominantly cardiologic phenotype characterized by conduction disease at an early age and RV involvement including right bundle branch block and/or RV tachycardias and arrhythmogenic RV cardiomyopathy phenocopies. A localized effect of desmin on the structure of the cardiac intercalated disks might contribute to disease pathogenesis.
van Tintelen
J Peter
JP
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. j.p.van.tintelen@medgen.umcg.nl
Van Gelder
Isabelle C
IC
Asimaki
Angeliki
A
Suurmeijer
Albert J H
AJ
Wiesfeld
Ans C P
AC
Jongbloed
Jan D H
JD
van den Wijngaard
Arthur
A
Kuks
Jan B M
JB
van Spaendonck-Zwarts
Karin Y
KY
Notermans
Nicolette
N
Boven
Ludolf
L
van den Heuvel
Freek
F
Veenstra-Knol
Hermine E
HE
Saffitz
Jeffrey E
JE
Hofstra
Robert M W
RM
van den Berg
Maarten P
MP
D000293:Adolescent; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology; D003893:Desmin / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index
D003893:Desmin