International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 42-53 http://medscipublisher.com/index.php/ijmms 49 8 Challenges and Future Directions 8.1 Genetic heterogeneity Familial hypertensive heart disease exhibits significant genetic heterogeneity, complicating the identification and interpretation of pathogenic mutations. For instance, Hypertrophic Cardiomyopathy (HCM), a common familial heart disease, involves mutations in over 11 genes encoding cardiac sarcomere proteins, with more than 1 400 variants identified. This vast genetic variability poses challenges in distinguishing between pathogenic mutations and benign variants, as well as those of uncertain significance (Maron et al., 2012). Similarly, the genetic basis of Pulmonary Arterial Hypertension (PAH) involves mutations in multiple genes, such as BMPR2 and ALK-1, with varying penetrance and expression, further complicating genetic analysis and risk prediction (Newman et al., 2004; Hinderhofer et al., 2014). 8.2 Challenges in data sharing and integration The integration and sharing of genetic data across different studies and populations remain significant hurdles. The variability in genetic findings across different ethnic groups, as seen in the prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial HCM, underscores the need for comprehensive and diverse genetic databases (Otsuka et al., 2012). Additionally, the identification of novel mutations and Variants of Unknown Significance (VUSs) in diseases like Familial Hypercholesterolemia (FH) highlights the necessity for collaborative efforts to classify these variants accurately (Futema et al., 2021). Standardizing genetic testing and interpretation protocols is crucial for effective data sharing and integration, which can enhance the reliability of genetic diagnoses and the development of precision medicine (Maron et al., 2012; Futema et al., 2021). 8.3 Translating gene mutations into precision medicine Translating genetic findings into clinical practice and precision medicine presents several challenges. The probabilistic nature of genetic testing results often complicates clinical decision-making, as seen in the case of HCM, where genetic testing is more effective for family screening rather than predicting prognosis (Maron et al., 2012). Moreover, the development of Genetic Risk Scores (GRSs) for conditions like hypertension has shown promise in stratifying disease risk and guiding treatment, but their application in clinical settings requires further validation and refinement (Olczak et al., 2021). The identification of specific gene mutations, such as those in the TNNT2, MYH6, and MYBPC3 genes associated with familial HCM, offers potential for biologically defined diagnoses and targeted therapies, yet translating these findings into effective treatments remains a complex task (Liu et al., 2021). Acknowledgments The author expresses gratitude to the two anonymous peer reviewers from Harbin Medical University and Nanjing Medical University for their rigorous and thorough review of this manuscript. The valuable feedback, critical evaluations, and detailed revision suggestions provided by the two reviewers have significantly contributed to the improvement of the manuscript's quality and academic standard. Conflict of Interest Disclosure The author affirms that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Abifadel M., and Boileau C., 2022, Genetic and molecular architecture of familial hypercholesterolemia, Journal of Internal Medicine, 293: 144-165. https://doi.org/10.1111/joim.13577 Al-Allaf F., Athar M., Abduljaleel Z., Taher M., Khan W., Ba-Hammam F., Abalkhail H., and Alashwal A., 2015, Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease, Gene, 565(1): 76-84. https://doi.org/10.1016/j.gene.2015.03.064 Austin M., Hutter C., Zimmern R., and Humphries S., 2004, Familial hypercholesterolemia and coronary heart disease: a HuGE association review, American Journal of Epidemiology, 160(5): 421-429. https://doi.org/10.1093/AJE/KWH237
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