Balkan Journal of Medical Genetics

MOLECULAR CHARACTERIZATION OF MICRORNA INTERFERENCE AND ARISTOLOCHIC ACID INTOXICATION FOUND IN UPPER TRACT UROTHELIAL CARCINOMA IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY: A SYSTEMATIC REVIEW OF THE CURRENT LITERATURE
Bašić D1*, Ignjatović I1, Janković Veličković Lj2, Veljković A3
*Corresponding Author: *Corresponding Authors: Dragoslav Bašić, Urology Clinic, University Clinical Center Niš, Faculty of Medicine, University of Niš, Niš, Serbia, Puškinova 2, 18000 Niš, Serbia, Email: basicdr@gmail.com
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DISCUSSION

In this study, we investigated a nonconsanguineous Han Chinese family with HCM. The proband’s father was also identified with HCM while his mother was normal. No chromosomal abnormalities were found in the proband. A novel heterozygous variant (c.3781_3785delGAGGC; p.Glu1261Thrfs*3) in the MYBPC3 gene was identified in the proband (Figure 5). This variant leads to a frameshift followed by the formation of a truncated MYBPC3 protein. The proband’s father also carries this variant in a heterozygous state while the proband’s mother does not harbor this variant. Segregation analysis showed that this heterozygous novel deletion is present among all the affected members as well as absent among all the unaffected members of this family. This variant is categorized as a “likely pathogenic” variant based on the guidelines of the American College of Medical Genetics and Genomics (ACMG) [25]. HCM is a very common disorder with extreme genotypic and phenotypic heterogeneity. Reduced penetrance and variable expressivity are often found in patients with HCM [27]. Additionally, intrafamilial phenotypic heterogeneity is also reported in HCM patients with the same genotype [27, 28]. However, most of the previous studies reported specific variations associated with the HCM phenotype in patients [29, 30]. HCM is a prevalent occurring disorder with an incidence rate of 1:500, among the general population worldwide [1, 31]. Hypertrophied and nondilated left ventricle (LV) are the main clinical symptoms for diagnosing HCM patients [32, 33]. Germline mutations in genes encoding sarcomere protein were identified in 60% of HCM patients with reduced penetrance and variable expressivity. Mutations in the MYBPC3 gene is most common among patients with inherited HCM (40%) [6, 23]. The MYBPC3 gene encodes the myosin-binding protein C of 1274 amino acids. It is a filament protein, present in cardiomyocytes. Myosin-binding protein C is involved in maintaining the structural organization of sarcomere and regulating contraction and relaxation. Previous studies reported that a majority (70%) of the germline mutations of MYBPC3 are truncating mutations [29-31]. HCM patients with truncating mutations in the MYBPC3 gene presented with severe clinical manifestations which carried the missense mutations in the MYBPC3 gene [32, 33]. In comparison with HCM patients with heterozygous mutations in the MYBPC3 gene, HCM patients harboring homozygous or compound heterozygous mutations in the MYBPC3 gene were reported to have severe clinical symptoms, followed by death due to heart failure at the neonatal stage [21]. It has been reported that the differences in disease mechanism is also correlated with the type of mutations (missense or truncating mutation) of the MYBPC3 gene in heart tissues [34, 35]. Truncating mutations in the MYBPC3 gene causes haploinsufficiency while missense mutations in MYBPC3 exerts a dominant negative effect. It has also been reported that truncated myosin-binding protein C is usually degraded by nonsense-mediated RNA decay [36, 37]. HCM is, genotypically and phenotypically, an extremely heterogenous cardiac disorder. Thus, a proper clinical diagnosis is very challenging. Genetic screenings and molecular diagnoses are very helpful for the clinicians in order to provide an accurate and timely diagnosis for the patients. Due to extreme genotypic and phenotypic heterogeneity, using whole exome sequencing is more accurate and less-time consuming than single gene sequencing or targeted next generation sequencing. Whole exome sequencing is a specific, accurate and faster technique allowing the clinicians to provide accurate clinical diagnosis of the HCM patients [38, 39]. Here, we reported a novel truncating variant in the MYBPC3 gene in a family with HCM. Acknowledgements We are thankful to the proband and all the family members for participating in our study. This study has been funded by Natural Science Foundation of Gansu Province (20JR5RA357). Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Authors’ contributions Designed the study: MB, ZZ and SB. Conducted acquisition and analysis of all the clinical data: YP, JX, YW, JZ, and LZ. WES pipelined and analyzed the data: CZ, and YJ. Selected patients and performed WES: CZ, and YJ. Supervised manuscript preparation and edited the manuscript: YP, JX, YW, ZZ, SB, and MB. Data availability All data used for the analyses in this report support the findings of this study are available upon reasonable request to the corresponding author

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