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 (>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

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

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives:CVON eDETECT consortium

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy

Dynamic location problems with limited look-ahead

Background Among the most frequently encountered mutations in dilated cardiomyopathy (DCM) are those in the lamin A/C (LMNA) gene. Our goal was to analyze the LMNA gene in patients with DCM and/or conduction disease referred to the cardiogenetics outpatient clinic and to evaluate the prevalence of LMNA mutations and their clinical expression. Methods and Results The LMNA gene was screened in 61 index patients. Eleven mutations (including 6 novel) were identified, mainly in the subgroup of familial DCM with cardiac conduction disease (3/10 index patients) and in patients with DCM and Emery-Dreifuss, Limb-Girdle, or unclassified forms of muscular dystrophy (7/8 index patients). In addition, a mutation was identified in 1 of 4 families with only cardiac conduction disease. We did not identify any large deletions or duplications.Genotype-phenotype relationships revealed a high rate of sudden death and cardiac transplants in carriers of the p.N 195K mutation. Our study confirmed that the p.R225X mutation leads to cardiac conduction disease with late or no development of DCM, underscoring the importance of this mutation in putative familial "lone conduction disease." Nearly one third of LMNA mutation carriers had experienced a thromboembolic event. Conclusions This study highlights the role of LMNA mutations in DCM and related disorders. A severe phenotype in p.N 195K mutation carriers and preferential cardiac conduction disease in p.R225X carriers was encountered. Because of the clinical variability, including the development of associated symptoms in time, LMNA screening should be considered in patients with DCM or familial lone conduction diseas

Desmin is essential for the structure and function of the sinoatrial node:implications for increased arrhythmogenesis

Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and β-catenin in structures we call “lateral intercalated disks” connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des-/-) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des-/mice. Upregulation of mRNA levels of both T-type Ca2+ current channels, Cav3.1 and Cav3.2, in the Des-/- myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des-/- mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis

Author Correction:The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy (Scientific Reports, (2020), 10, 1, (9819), 10.1038/s41598-020-66656-9)

The title in the original version of this Article contained a typographical error of ‘unresponsive’. The error has now been corrected in the PDF and HTML versions of the Article