Scope: To identify a possible genetic variant implicated in the cardiac phenotype of one family displaying in father and son hypertrophic cardiomyopathy (HCM). Methods: A 51-years old patient with mid-ventricu-lar non-obstructive biventricular HCM, implantable defibrillator in secondary prevention after sustained ventricular tachycardias and his son, 31-years old with sub-aortic diaphragmatic membrane operated at 11 years old and concentric left ventricular hypertrophy, present at surgery, but progressing in time after inter-vention have been genetically tested. Genomic DNA was isolated from peripheral whole blood and targeted sequencing was performed on an Illumina MiSeq plat-form using the TruSight Cardio Sequencing Kit (Illu-mina) targeting 174 genes. The significance of the va-riants was determined based on allele frequency (AF) and in silico prediction tools. For variants classification we used the criteria issued in 2015 by American Colle-ge of Medical Genetics and Genomics and the Associa-tion for Molecular Pathology.
Results: After discarding the variants with AF>1% in the general population and the variants classified as benign or likely benign, the heterozygous sequen-ce c.611A>G (p.Tyr204Cys) was retained for further analysis. In both subjects we identified the mentioned variant in the gene encoding for thioredoxin reductase (TXNRD2), a missense variant that replaces tyrosine-a moderate conserved amino-acid- with cysteine at co-don 204. All the silico prediction algorithms suggest that the effect of this change is likely to be deleterious. The criteria supporting the pathogenicity of the variant are: one moderate evidence-PM2- the low frequency of the variant in population databases (0.00006 in Exome Aggregation Consortium), as well as one supporting evidence-PP3-the harmful effects of the gene suppor-ted by different in silico algorithms. The lack of functi-onal studies and insufficient reported cases in literature in relation with HCM, classify this as a variant with un-certain significance.
Conclusions: Our study reports for the first time the identification of c.611A>G variant in the TXNRD2 gene in a Romanian family with HCM. Currently, the TXNRD2 gene has no well-established disease associ-ation. Further family segregation analysis and functio-nal studies are necessary to support reclassification of the variant. This work was supported by CREDO Project – ID: 49182, financed by the National Authority of Scienti-fic Research and Innovation, on behalf of the Roma-nian Ministry of European Funds- through the Secto-ral Operational Programme “Increasing of Economic Competitiveness”, Priority Axis 2, Operation 2.2.1 (SOP IEC -A2-0.2.2.1-2013-1) cofinanced by the Euro-pean Regional Development Fund