Background

Genetic testing has emerged as an important diagnostic tool allowing to decipher the molecular underpinnings of inherited cardiac disorders (ICD). Despite development of next generation sequencing (NGS) techniques leading to efficient and time-saving diagnostic workup, molecular diagnosis in patients with suspected ICD and especially in first degree members is only insufficiently applied in clinical practice. We here present first results of a consequent genetic testing strategy according to current guidelines in patients that were referred for ICD at Ulm University Medical Center.

Methods

Whole-Exom-Sequencing using a panel of 143 genes associated with ICD was performed in 184 patients suffering either from cardiomyopathies (132/184 (72%) patients), arrhythmia syndromes (41/184 (22%) patients), or unexplained sudden cardiac death (SCD, 11/184 (6%) ) between 2018 and 2021 at Ulm University Medical Center. Identified genetic variants were evaluated using HGMD professional, ClinVar and LVOD. As reference genome hg19, NCBI was used. Impact of identified variances on protein function was assessed by the in-silico software tools MetaLR, MetaSVM, Sift Mutationstaster. According to current guidelines identified variances were classified in pathogenic (class V), likely pathogenic (class IV), variance of unknown significance (VUS, class III).   

Results

In 101/184 (55%) patients genomic variances (class III-V) in ICD-associated genes were identified. (Likely) pathogenic variants were found in 52/184 (28%) patients, whereas VUS were found in 49/184 (27%). Compound mutations and/or variances were found in 29/184 (16%) patients. Frameshift mutations were found in 15/184 (%) patients resulting in 6/15 stop codons. Most common gene locus in patients with dilatative cardiomyopathy (DCM) was TTN, in patients with hypertrophic cardiomyopathy (HCM) MYBPC3, in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) PKP2, in patients with Brugada-Syndrome (BrS) SCN5A and in patients with Long-QT syndrome (LQTS) KCNH2. Interestingly, in patients with survived unexplained SCD most frequent locus was DSC2 followed by SCN5A.

Conclusion

Consequent genetic testing strategy in patients with suspected inherited cardiac disease led to identification of genetic variances (class III-V) in the majority of patients enabling individualized  and disease-specific counselling of patients suffering from ICD.