**3. Genetic testing**

The advent of next-generation sequencing enables cost-effective genetic testing in familial DCM which can define the precise genetic cause of disease. Genetic testing can also help optimize risk stratification and assess prognostics of patients and their relatives. With the identification of a pathogenic mutation and early diagnostic certainty, clinical management of affect individuals could be tailored and patients' survival can be improved. One best example is related to clinical practice of early intervention of DCM patients with L*MNA* mutations. *LMNA*-related DCM usually accompanied by significant conduction system disease, atrial fibrillation, ventricular tachycardia, and sudden cardiac death (SCD). Thus, *LMNA* mutations are often associated with a higher disease penetrance and more severe morbidity and high mortality [60]. Studies in several different cohorts of DCM patients with *LMNA* mutations identified non-missense mutations, LVEF<45% and higher

AV blocker as significant risk factors for disease malignancy [61, 62]. Because of this well-determined genotype–phenotype knowledge, an actionable prognostic genotype–phenotype association, implementation of a lower threshold and earlier implantable cardioverter defibrillator (ICD) therapy than current guidelines recommend in patients with LMNA mutations, was demonstrated to significantly improve patient outcome and survival [63].

Based on the Genetic Testing Registry (https://www.ncbi.nlm.nih.gov/gtr/), there are from 40 to 80 genes included in the testing panels for most commercially available genetic testing for DCM. In familial DCM, the yield of genetic testing, resulting in identification of pathogenic mutations, can thus far reach up to 40%, in a comparable level to that of other inherited cardiac disorders such as HCM and long QT syndrome. The sensitivity of genetic testing is compromised partially due to that not all genes implicated in DCM are included in the gene panels for testing. This is especially the case for those identified from sporadic DCM cases or single family. Furthermore, limited by human genetics approaches that heavily rely on pedigree availability and candidate gene approaches, variants for more than half of familial DCM cases have not been identified yet. As technique advances in genetics of cardiomyopathy, identification of the remaining genetic causes in inherited DCM cases and elucidation of the underlying pathogenic mechanisms leading to the phenotype are evolving rapidly. Targeted gene panels for genetic testing are increasing in an unprecedented scale. With further characterization and functional validation, the ever expanding gene panels of genetic testing promise to increase the rate of positive identification and provide individuals and families with a more comprehensive and conclusive genetic testing.
