New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis

Abstract

<jats:p>Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.</jats:p>

X‐chromosomal inactivation patterns in women with Fabry disease

“… a According to http://www.dbfgp.org . b 1 = benign, 2 = likely benign, 3 = VUS, 3+ = VUS with probable pathogenicity, 4 = likely pathogenic, 5 = pathogenic (Kolokotronis et al, 2020 ; Richards et al., 2015 ). c active site mutation = variant in the active site of the alpha‐galactosidase A, buried mutation = variant close to active site, other mutation = variant outside the active site (Rickert et al, 2020 ).…”

“…For individual classification, the Fabry database was used ( http://www.dbfgp.org ). (2) Based on the five pathogenicity classes of sequence variants according to the American College of Medical Genetics and Genomics (ACMG) (Richards et al, 2015 ), i.e., benign (equivalent to “class 1”), likely benign (“class 2”), VUS (“class 3”), VUS with probable pathogenicity (“class 3+”) (Kolokotronis et al, 2020 ), likely pathogenic (“class 4”), and pathogenic (“class 5”). The allocation to these classes was achieved by evaluating the information from Alamut Visual version 2.11 (Interactive Biosoftware, Rouen, France) providing the data of various population and mutation databases, different prediction tools, as well as information from the literature.…”

“…Of the 70/95 (74%) women carrying missense variants, the majority had "other" mutations (44/70, 62%). 18/95 (19%) women carried one of the sequence variants D313Y (9/95, 9%), A143T (8/95, 8%), and W399S (1/95, 1%), which are currently assumed apathogenic (Lenders et al, 2016;Lukas et al, 2016;Oder et al, 2016). Clinical data of the main patient cohort ("Group I", n = 77) was assessed separately from the data of these women ("Group II", n = 18).…”

Non-pharmaceutical Interventions for Hypertrophic Cardiomyopathy: A Mini Review

“…Compared with familial HCM, individuals with non-familial HCM have late-onset and less severe disease (78)(79)(80). The correlation between genotype and phenotype is not consistent because of the complex genetic basis, epigenetics and other mechanisms for regulating gene expression, environmental conditions such as non-sarcomere genetic variations, and more importantly, the overlap among several disease gene groups (81)(82)(83)(84)(85). These factors make genetic testing and result interpretation particularly challenging.…”

Clinical Considerations for a Family with Dilated Cardiomyopathy, Sudden Cardiac Death, and a Novel TTN Frameshift Mutation

“…More than 35% of patients clinically affected by DCM harbor either a heterozygous or homozygous mutation in at least one of several genes, encoding for sarcomeric, cytoskeletal, or nuclear proteins [ 3 ]. The percentage of molecularly confirmed cases is today not easily assessed, mainly because of phenotypic overlapping, but has recently been reported to be as high as 69% in whole exome studies [ 4 ]. In spite of this, the average clinical sensitivity of genetic testing for DCM, using next-generation sequencing (NGS), can be estimated to be much lower, in particular around 37% [ 5 ].…”