Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

Figure 1. Pedigrees of the described families. (A) Family A has a South Asian origin. The male index patient (II-1) received his diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) at the age of 12. (B) Family B has a Russian origin. Circles represent females, squares males. Black-filled symbols indicate a cardiac phenotype and white symbols indicate healthy family members. +/− indicates heterozygous, +/+ homozygous, and +/0 hemizygous status. Index patients are marked with an arrow. Obligate carriers are shown with a black dot in the pedigree symbol.

Figure 2. Clinical data of II-I, Family A. (A–B) Cardiac magnetic resonance imaging (MRI) revealed a dilated right ventricle with reduced global function and segmental bulging. Hematoxylin and eosin (C) and trichrome staining (D) of a right-ventricular biopsy revealed subendocardial fibrosis and degeneration of cardiomyocytes. Scale bars represent 50 µm. (E–F) Right axis deviation, at the age of 12 years still incomplete, later complete right bundle branch block, inverted T-waves in the right precordial leads and non-sustained ventricular tachycardia were present in the 12-lead electrocardiogram (ECG).

Figure 3. Speckle tracking echocardiography (STE) demonstrated dyssynchrony of the septal and right ventricular free-wall segments (see also Video S1, Supplementary Data).

Figure 4. Clinical data of Family B. (A–I) Cardiac magnetic resonance imaging (MRI) of index patient (II-2, Family B). Asterisk indicates thinning and aneurysmal protrusion of right ventricular wall (A–C). Arrows indicate ischemic changes in left ventricle (D,F). Dotted arrows indicate thrombosis in the right ventricle (B,E). Ellipse shows fibrosis of the right ventricle (F). Triangle demonstrates LV non-compaction (G–I). Rhombus demonstrates RV non-compaction (G,I). (J) Epsilon waves were present in the 12-lead ECG. (K) Tachycardia was present in the Holter monitoring-ECG.

Figure 5. Cardiac magnetic resonance imaging (MRI) of the I-1 (A), I-2 (B,D–F), and II -1 (C) of Family B. Asterisk indicates non-compaction layer.

Figure 6. Genetic analysis of II-1 (Family A). (A) Integrated genome view of exon 4 in DSG2 of patient II-1. (B) Electropherogram of exon 4 in DSG2 (II-1). The mutation DSG2–c.378+1G>T is affecting the donor splice site and is found in a homozygous status. (C) Karyoview of II-1. LOH = loss of heterozygosity. (D) Detailed ideogram of human chromosome 18 revealing a 15.6 Mb loss of heterozygosity (LOH).

Figure 7. (A–I) Genetic analysis of Family B. (A) Integrated genome view of exon 14 in DSG2 of patient II-2 (Family B). (B–F) Partial electropherograms of DSG2 exon 14 revealed for I-1 two heterozygous variants p.L772X and p.R773K (B), for I‑2 a wild-type sequence (C), for II-1 the heterozygous variant p.R773K (D), for II-2 hemizygous p.L772X (E), and for II-3 hemizygous p.R773K (F). (G) Karyoview of II-2 (Family B). LOH = loss of heterozygosity. (H–I) Detailed ideogram of human chromosome 18 revealing an additional deletion on the second chromosome affecting nearly the complete DSG2 gene.