Genotype-Phenotype Correlation: A Triple DNA Mutational Event in a Boy Entering Sport Conveys an Additional Pathogenicity Risk

Abstract

The purpose of this paper is to present a clinical and laboratory study of a family, in which a 12-year-old boy was examined to assess his health status before starting competitive sports. A variety of clinical and instrumental tests were used to evaluate the status of the heart and its functions. Using Sanger sequencing (SS), we sequenced six related genes to verify suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) hypothesized at the cardiac assessment and, subsequently, by a next-generation sequencing (NGS)-based multi-gene panel for more paramount genetic risk of sudden cardiac death (SCD) assessment. SS revealed two variants in the PKP2 gene, one was inherited from the father and the other from the mother. The analysis on a large panel of genes (n = 138), putatively associated with sudden cardiac death, revealed, in the proband, a third variant in a different gene (DES) that encodes the protein desmin. Our results indicate that: i) NGS revealed a mutational event in a gene not conventionally screened as a first-line test in the presence of clinical suspicion of the arrhythmic disease; ii) a plurality of variants in different genes in the same subject (the proband) may increase the risk of heart disease; iii) in silico analysis with various methodological software and bioinformatic prediction tools indicates that the cumulative effects of the three variants in the same subject constitute an additional risk factor. This case report indicates that more pathogenic variants or likely pathogenic variants can contribute to the clinical phenotype of an individual, thereby contributing to the diagnosis and prognosis of inherited heart diseases.

Molecular Basis of Inflammation in the Pathogenesis of Cardiomyopathies

“…Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by a fibro-fatty replacement of the right ventricular and/or left ventricular myocardium, which leads to anatomical, contractility and electrical rhythm abnormalities with life-threatening complications [18,19]. The predominant cause of the dominant-right ACM (ARVC) is represented by mutations in genes that encode components of desmosomes, the adhesive junctions that connect cardiomyocytes, and it leads to the loss of efficient electrical coupling with a consequent increased arrhythmic burden [20].…”

Combined PTPN11 and MYBPC3 Gene Mutations in an Adult Patient with Noonan Syndrome and Hypertrophic Cardiomyopathy

“…Here, we report a non-severe, familial case of non-obstructive HCM, associated with mild clinical features of NS, diagnosed by a multidisciplinary team of expert cardiologists and geneticists. Cardiac and non-cardiac red flags (RF) represent important diagnostic markers that permit to suspect a specific cause of cardiomyopathy and a distinction between sarcomeric and non-sarcomeric types [ 1 , 3 ], and genetic testing represents a necessary diagnostic tool for performing a definitive etiological diagnosis [ 15 , 16 , 17 , 18 ]. Indeed, the association between HCM and pulmonary stenosis and/or dysmorphisms should always raise suspicion of genetic syndromes, even in adults.…”

The Hidden Fragility in the Heart of the Athletes: A Review of Genetic Biomarkers

“…Twelve publications, ranging from 2008 to 2020, were found, meeting the above-mentioned eligibility criteria, in principle. Seven papers depicted eight single case reports of athletes of Caucasian origin [ 39 , 40 , 41 , 42 , 43 , 44 ]. However, we excluded three among seven, because they did not report technologies used to perform genetic test and/or the specifications of the identified genetic variants [ 39 , 40 , 41 ].…”

“…However, we excluded three among seven, because they did not report technologies used to perform genetic test and/or the specifications of the identified genetic variants [ 39 , 40 , 41 ]. The remaining are four case reports of white, asymptomatic, amateur athletes, who showed ECG anomalies during the pre-participation screening requiring a thorough cardiac evaluation in tertiary referral centres ( Table 2 ) [ 24 , 42 , 43 , 44 ]. Of note, an athlete reported that two relatives died suddenly at a young age [ 44 ].…”

“…Similarly, post-mortem genetic studies identified molecular alterations that can be causative or con-causative of SCD in athletes [ 36 , 37 , 38 ]. However, in recent years, several studies have addressed the issue of using genetic testing in athletes showing instrumental abnormalities (ECG and/or echocardiogram and/or cardiac magnetic resonance) or family history of cardiomyopathy or SCD, with the aim of early diagnosis of life-threatening cardiac genetic disorders [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ].…”