BACKGROUND: Nonischemic cardiomyopathies are frequently caused by genetic mutations in about 100 different genes. The cardiomyopathy-associated gene DES encodes the intermediate filament protein desmin, which is important for the structural integrity of the cardiomyocytes. METHODS: Using a next-generation sequencing approach, we performed cascade screening of a previously identified heterozygous DES missense mutation (c.380G>C, p.R127P) segregating in a large 6-generation Kuwaiti family, where several members died from sudden cardiac death or developed different cardiomyopathies, partially in combination with conduction disease and atrial fibrillation. DES -p.R127P affects a highly conserved position and is absent or super rare in different genetic human population databases. In silico predictions support the pathogenicity of DES -p.R127P. To investigate the detrimental impact of desmin-p.R127P, we performed cell transfection experiments using different cell lines and cardiomyocytes derived from induced pluripotent stem cells in combination with confocal microscopy. RESULTS: These experiments demonstrated a severe desmin filament assembly defect leading to aberrant cytoplasmic desmin aggregates, even when co-expressed with wild-type desmin. Atomic force microscopy analysis supported the filament assembly defect of mutant recombinant desmin-p.R127P. To investigate the physicochemical impact of the amino acid at this position, we generated a set of 20 different variants and analyzed their filament formation in cell culture. Most of these variants disturbed the filament assembly comparable to p.R127P. CONCLUSIONS: In summary, we present and characterize a likely pathogenic missense mutation DES -p.R127P, which causes high cardiac mortality and morbidity in the described family. Our study has relevance for the interpretation and classification of further DES variants and might be helpful for the genetic counseling of patients and their relatives in future cases.

The etiology of Kawasaki disease remains unknown despite extensive studies. Some researchers suggest that it is caused by an infectious agent. This is a case report where a patient with incomplete Kawasaki disease was found to have evidence compatible with acuteMycoplasma pneumoniaeinfection. This is one of the several case reports linkingMycoplasma pneumoniaeto Kawasaki disease as a possible trigger. This is perhaps due to a superantigen or is mediated by some other mechanism. Accurate and timely testing forMycoplasma infectionsis difficult and has its limitations. Despite this,Mycoplasma pneumoniaeshould be considered in the differential and workup for Kawasaki disease.

BACKGROUND: Marked intellectual and neurodevelopmental delay (INDD) was noted in 6 unrelated patients diagnosed with RYR2 -related catecholaminergic polymorphic ventricular tachycardia (CPVT) from a single center. Patients exhibited similar distinct phenotypic features not previously described. We aimed to determine the prevalence of INDD in CPVT, compare clinical characteristics between patients with CPVT with and without INDD, and investigate the possibility of a unique neurocardiac CPVT phenotype. METHODS: Retrospective combined review of patients with RYR2 -related CPVT diagnosed ≤18 years with and without INDD from a single center and the International Pediatric CPVT Registry. Patients with hypoxic ischemic insult were excluded unless INDD preceded injury. RESULTS: Among a total of 168 patients, INDD was reported in 19 (11.3% [95% CI, 7.0%–17.1%]). When compared with cases without INDD, patients with INDD exhibited distinct features including (1) younger age at onset of symptoms (median 7.0 versus 10.0 years; P =0.04); (2) higher frequency of atrial tachyarrhythmias (84.2% versus 16.3%, P <0.001); (3) atrial or ventricular tachycardia without adrenergic stimulation (81.3% versus 2.2%, P <0.001, 31.6% versus 4.5%, P =0.001 respectively); (4) cardiac structural changes or systolic dysfunction (36.8% versus 1.3%, P <0.001); and (5) higher incidence of cardiac arrest or sudden death after diagnosis (26.3% versus 2.7%, P =0.001). INDD-related RYR2 genetic variants clustered within the central and channel domains and may be specific to certain variants. CONCLUSIONS: This study demonstrates a wider spectrum of RYR2 -related disease, with a subset associated with extracardiac manifestations. Certain RYR2 variants may lead to a neurocardiac phenotype with distinct features that are important to recognize, as these patients may be at higher risk.