The role of genetics in cardiovascular disease: arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiomyopathy characterized by frequent ventricular arrhythmias and progressive ventricular dysfunction. Risk of sudden cardiac death is elevated in ACM patients and can be the presenting symptom particularly in younger individuals and athletes. This review describes current understanding of the genetic architecture of ACM and molecular mechanisms of ACM pathogenesis. We consider an emerging threshold model for ACM inheritance in which multiple factors including pathogenic variants in known ACM genes, genetic modifiers, and environmental exposures, particularly exercise, are required to reach a threshold for disease expression. We also review best practices for integrating genetics—including recent discoveries—in caring for ACM families and emphasize the utility of genotype for both management of affected individuals and predictive testing in family members

Technical note Communication: Frequency ofchanging solid-walled cages does not affect pentobarbitone-induced sleeping time in rats and mice

The effects on pentobarbitone-induced sleeping time of daily cage changing or once every three days versus no changing for 15 days, was investigated in mice and rats, respectively. The animals were housed individually in cages with solid floors and a layer of wood shavings as bedding. Sleeping times were not affected by the frequency of cage changing

Quantitative Approach to Fragmented QRS in Arrhythmogenic Cardiomyopathy: From Disease towards Asymptomatic Carriers of Pathogenic Variants

Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM (n = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis (n = 57, 17%) and control subjects (n = 58, 17%) were included. Quantitative fQRS (Q-fQRS) was defined as the total amount of deflections in the QRS complex in all 12 electrocardiography (ECG) leads. Q-fQRS was scored by a single observer and reproducibility was determined by three independent observers. Q-fQRS count was feasible with acceptable intra- and inter-observer agreement. Q-fQRS count is significantly higher in patients with definite ACM (54 ± 15) and pathogenic variant carriers (55 ± 10) compared to controls (35 ± 5) (p < 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia (p = 0.701) at baseline or during follow-up (p = 0.335). Both definite ACM patients and pathogenic variant carriers not fulfilling ACM diagnosis have a higher Q-fQRS than controls. This may indicate that increased Q-fQRS is an early sign of disease penetrance. In concealed and early stages of ACM the role of Q-fQRS for risk stratification is limite

Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes:The Importance of Functional Studies above Prediction

Genetic variants in gene-encoding proteins involved in cell-cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype-phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (&gt;5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype-phenotype correlations, we separate variants into 'protein reducing' or 'altered protein' variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation

The value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by risk of malignant ventricular arrhythmias (VA). ARVC is diagnosed using an array of clinical tests in the consensus-based task force criteria (TFC), one of which is genetic testing. OBJECTIVE: To investigate the value of genetic testing in diagnosing ARVC and its relation to the occurrence of first malignant VA. METHODS: A multicenter cohort of ARVC patients was scored using the revised 2010 TFC with and without genetic criterion, analyzing any resulting loss or delay of diagnosis. Malignant VA was defined as sustained ventricular arrhythmia (≥30s duration at ≥100 bpm or requiring intervention). RESULTS: We included 402 subjects (55% male, 54% proband, 40 [27-51] years old at presentation) who were diagnosed with definite ARVC. A total of 232 (58%) subjects fulfilled genetic testing criteria. Removing the genetic criterion caused loss of diagnosis in 18 (4%) patients (11/216 [5%] probands, 7/186 [4%] relatives), and delay of diagnosis ≥30 days in 22 (5%) patients (21/216 [10%] probands, 1/186 [0.5%] relative). A first malignant VA occurred in no patients who lost diagnosis and in 3 patients (3/216 [1%] probands and no relatives) during their diagnosis delay, none fatal. Time to event analysis showed no significant difference in time from diagnosis to malignant VA between pathogenic variant carriers and non-carriers. CONCLUSION: Disregarding the genetic criterion of the TFC caused loss or delay of diagnosis in 10% (n=40/402) of ARVC patients. Malignant VA occurred in 1% (n=3/402) of cases with lost or delayed diagnosis, none fatal

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Diagnostic Task Force Criteria Impact of New Task Force Criteria

Background-Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Diagnostic Task Force Criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international task force modified criteria to improve diagnostic yield. A comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups was conducted. Methods and Results-In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS ≥55 ms, ventricular tachycardia with left bundle-branch block morphology and superior axis, and genetic criteria. Three groups were studied: (1) 105 patients with proven ARVD/C according to 1994 TFC, (2) 89 of their family members, and (3) 39 patients with probable ARVD/C (ie, 3 points by 1994 TFC). All were screened for pathogenic mutations in desmosomal genes. Three ARVD/C patients did not meet the new sharpened criteria on structural abnormalities and thereby did not fulfill new TFC. In 62 of 105 patients with proven ARVD/C, mutations were found: 58 in the gene encoding Plakophilin2 (PKP2), 3 in Desmoglein2, 3 in Desmocollin2, and 1 in Desmoplakin. Three patients had bigenic involvement. Ten additional relatives (11%) fulfilled new TFC: 9 (90%) were female, and all carried PKP2 mutations. No rel

Terminal osseous dysplasia with pigmentary defects and cardiomyopathy caused by a novel FLNA variant

Terminal osseous dysplasia with pigmentary defects (TODPD), also known as digitocutaneous dysplasia, is one of the X‐linked filaminopathies caused by a variety of FLNA‐variants. TODPD is characterized by skeletal defects, skin fibromata and dysmorphic facial features. So far, only a single recurrent variant (c.5217G>A;p.Val1724_Thr1739del) in FLNA has found to be responsible for TODPD. We identified a novel c.5217+5G>C variant in FLNA in a female proband with skeletal defects, skin fibromata, interstitial lung disease, epilepsy, and restrictive cardiomyopathy. This variant causes mis‐splicing of exon 31 predicting the production of a FLNA‐protein with an in‐frame‐deletion of 16 residues identical to the miss‐splicing‐effect of the recurrent TODPD c.5217G>A variant. This mis‐spliced transcript was explicitly detected in heart tissue, but was absent from blood, skin, and lung. X‐inactivation analyses showed extreme skewing with almost complete inactivation of the mutated allele (>90%) in these tissues, except for heart. The mother of the proband, who also has fibromata and skeletal abnormalities, is also carrier of the FLNA‐variant and was diagnosed with noncompaction cardiomyopathy after cardiac screening. No other relevant variants in cardiomyopathy‐related genes were found. Here we describe a novel variant in FLNA (c.5217+5G>C) as the second pathogenic variant responsible for TODPD. Cardiomyopathy has not been described as a phenotypic feature of TODPD before