PMC9580399_01
The clinical and sequencing data of this family. (A) The genealogy of this family. Squares indicate male family members and circles indicate female members. The black symbols represent the clinically affected members. The white symbols represent unaffected and healthy members. The arrow shows the proband. Crossed-out symbols stand for deceased relatives. +- represents heterozygous DES-p. E434K variant. + / + represents a wild type. (B) ECG of the proband. (C) Sanger DNA sequencing chromatogram detected a heterozygous mutation (c.1300G > A; p. E434K) of DES gene in the proband. (D) Alignment of multiple DES protein sequences across species. Letters in red show the E434 site is evolutionarily conserved.
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F1
The proband (II-5) was a 50-year-old woman from the central south region of China (Hunan Province) (Figure 1A). The electrocardiogram (ECG) records showed sinus rhythm, over-load volume of the left ventricle (Figure 1B), but this is not typical for Brugada. The results of ambulatory ECG (AECG) have been shown in Supplementary Figure 1. The rest of her family members were healthy and no other malformations were observed in this family (Table 1 and Figure 1A). E434K) of the DES gene (NM_001927.4) may underlie the genetic factor of this family (Figure 1C). Alignment of desmin amino acid sequences revealed that E434 is conserved in different species (Figure 1D).
The bioinformatics analysis of mutations. Structure prediction of the mutant protein. The wild-type DES (DES-WT) protein structure and the p. E434K mutant DES (DES-p. E434K) protein structure were predicted by SWISS-MODEL online software. (A) Red arrow shows the charged change of desmin protein. In the DES-WT protein, E434 is hydrophobic with S432 and R436. In the DES-p.E434K protein, the hydrophobic effect with S432 disappeared after E434K mutation, while the hydrophobic effect with R436 remained (B) MetaDome server was used to identify the intolerant regions in DES. As depicted, the affected nucleotide/residue is located in an intolerant region. (C) Overview of all reported phenotypes caused by DES mutations. ARVC, arrhythmogenic right ventricular cardiomyopathy; AVP, autophagic vacuolar pathology; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular non-compaction; RCM, restrictive cardiomyopathy; SCD, sudden cardiac death; SUD, sudden unexplained death.
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F2
Coronary angiography suggested a myocardial bridge and mild stenosis of the left anterior descending artery (Supplementary Figure 2). Modeling of proteins before and after missense mutation was performed by the SWISS-MODEL.1 Results revealed that the missense mutation at E434K may lead to the changing of protein surface charge as marked by red arrow in Figure 2A. In the mutated desmin protein, the hydrophobic effect with S432 disappeared after E434K mutation, while the hydrophobic effect with R436 remained (Figure 2A). Furthermore, MetaDome software2 indicated that the affected residue, E434, is located in an intolerant region of desmin (Figure 2B).