**5. Conclusions**

The ultimate goal of elucidating genetic basis for DCM is for early disease diagnosis, early disease intervention and treatment. To date, pathogenic mutations in more than 50 genes are associated with DCM. However, these mutations can only explain about 40–50% of familial DCM cases, and the genetic architecture of DCM still remains incompletely understood. Future research directions rely on technique advances for identification of the remaining up to 60% of genetic causes in familial DCM cases. After identifying the genetic causes, functional characterization and validation studies are needed to confirm the pathogenic variants. Extensive studies on delineation of genotype–phenotype relationships are necessary to address currently unmet issues for translational research. Further dissecting genetic pathways linked to DCM and elucidating the pathogenic mechanisms leading to the phenotype can provide valuable insights into the understanding of disease pathophysiology, laying solid foundation for future development of groundbreaking therapeutics.

Gene-based therapies, such as gene replacement, exon skipping and recent evolutionarily developed CRISPRA/Cas9 based genome-editing techniques that directly target at the underlying genetic mutations responsible for the DCM disease progression, have led to several clinical trials which have produced promising results. Thus, the last decade has witnessed encouraging advances in the development of genotype-targeted, personalized therapies. While the progress is promising, several technical issues need to be thoroughly assessed before implementation in clinical practice. For example, current gene delivery system mostly adapt the AAV system because of its many advantages such as long term transgene expression and choice of appropriate serotype for heart enriched expression. One primary limitation for this system, however, is that there exists certain level of anti-AAV antibodies in general human population causing the immunogenicity issue which can potentially lead to development of myocarditis [70, 90–92]. While the efficiency for exogenous delivery of preprocessed RNAs or oligonucleotides for trans-splicing or exon skipping needs to be further improved, a major concern of off-target issue needs to be seriously addressed for the highly efficient AAV9 mediated CRISPR/Cas9 genome editing system. Novel approaches are desirable to comprehensively evaluate any potential off-target mutagenesis in the heart and other tissues for future clinical application.

**115**

**Author details**

Qingdao, China

† Equal contribution.

Jing Zhong1†, Li-Ping Li1†, Jian-Feng Zhou2,3 and Yong-He Ding4

Marine Science and Technology (Qingdao), Qingdao, China

of Qingdao University, Qingdao University, Qingdao, China

\*Address all correspondence to: dingyonghe@qdu.edu.cn

provided the original work is properly cited.

University, Qingdao University, Qingdao, China

1 School of Basic Medicine, The Biomedical Sciences Institute of Qingdao

2 Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,

3 Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for

4 The Affiliated Hospital of Qingdao University, The Biomedical Sciences Institute

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*

*Genetic Determinant of Familial Dilated Cardiomyopathy and Genotype-Targeted Therapeutic…*

*DOI: http://dx.doi.org/10.5772/intechopen.94434*
