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The Desmin (DES) Mutation p.A337P Is Associated with Left-Ventricular Non-Compaction Cardiomyopathy.

ABSTRACT: Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, DES-p.A337P was identified in the genomes of both patients, whereas only the index patient carried DSP-p.L1348X. DES encodes the muscle-specific intermediate filament protein desmin and DSP encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of DES mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this DES mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the DES gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present.

SUBMITTER: Kulikova O

PROVIDER: S-EPMC7835827 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The Desmin (<i>DES</i>) Mutation p.A337P Is Associated with Left-Ventricular Non-Compaction Cardiomyopathy.

Kulikova Olga O Brodehl Andreas A Kiseleva Anna A Myasnikov Roman R Meshkov Alexey A Stanasiuk Caroline C Gärtner Anna A Divashuk Mikhail M Sotnikova Evgeniia E Koretskiy Sergey S Kharlap Maria M Kozlova Viktoria V Mershina Elena E Pilus Polina P Sinitsyn Valentin V Milting Hendrik H Boytsov Sergey S Drapkina Oxana O Drapkina Oxana O

Genes 20210119 1

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, <i>DES</i>-p.A337P was identified in the genomes of both patients, whereas only the index patient carr ...[more]

PMID: 33478057

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Project description:AimsLeft ventricular non-compaction cardiomyopathy (LVNC) is a poorly understood entity resulting in heart failure. Whether it is a distinct form of cardiomyopathy or an anatomical phenotype is a subject of discussion. The current diagnosis is based on morphologic findings by comparing the compacted to non-compacted myocardium. The study aimed to compare demographic and prognostic variables of patients with dilated cardiomyopathy (DCM) and LVNC. Emphasis was given to cardiac magnetic resonance (CMR) imaging analysis. Data on survival were also assessed.Methods and resultsWe retrospectively evaluated the characteristics and outcomes of 262 non-ischaemic cardiomyopathy patients with LVNC and DCM phenotypes. Petersen's CMR criteria of non-compacted to the compacted myocardial ratio 2.3 were used to diagnose LVNC. The primary endpoint was a composite endpoint of major adverse cardiovascular events comprising cardiovascular-related death, left ventricular assisted device implantation, or heart transplantation. A total of 262 patients with CMR data were included in the study. One hundred fifty-five patients who fulfilled CMR criteria were diagnosed as LVNC. CMR findings revealed that LVNC patients had higher left ventricular end-diastolic (137.2 ± 51.6, 116.8 ± 44.6, P = 0.002) and systolic volume index (98.4 ± 49.5, 85.9 ± 42.7, P = 0.049). Cardiac haemodynamics, cardiac output (5.61 ± 2.03, 4.96 ± 1.83; P = 0.010), stroke volume (73.9 ± 28.8, 65.1 ± 25.1; P = 0.013), and cardiac index (2.85 ± 1.0, 2.37 ± 0.72; P < 0.0001), were higher in LVNC patients. Of all the 249 patients, 102 (40.9%) patients demonstrated late gadolinium enhancement (LGE). According to Petersen's criteria, the Kaplan-Meier survival outcome did not reveal significant differences (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: [0.89-2.63], P = 0.11). The presence or pattern of LGE did not show significant importance for endpoint-free survival. Most of the sub-epicardial LGE pattern was found in LVNC patients (94.4%). When receiver operator characteristics analysis was applied to NC/C ratio to discriminate the primary endpoint, a higher NC/C ratio of 2.57 was associated with adverse events (HR: 1.90, 95% CI: [1.12-3.24], P = 0.016).ConclusionsOur study questions the criteria being used for the diagnosis of LVNC. Further evaluation of CMR variables and association of these findings with demographic variables and survival is mandatory.

Dataset Information

The Desmin (DES) Mutation p.A337P Is Associated with Left-Ventricular Non-Compaction Cardiomyopathy.

Publications

The Desmin (<i>DES</i>) Mutation p.A337P Is Associated with Left-Ventricular Non-Compaction Cardiomyopathy.

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