New Missense Mutation Gly238Ala in the TBX5 Gene and Its Phenotypical Characteristics

The TBX5 gene encodes the T-box transcription factor 5 (Tbx5) involved in the regulation of developmental processes in both vertebrates and invertebrates. Mutations in this gene cause rare monogenic Holt–Oram syndrome (HOS) characterized by skeletal anomalies of the upper limbs, a congenital heart defect, and/or сardiac сonduction system diseases. Next generation sequencing (NGS) made it possible to detect a new nucleotide variant c.713G>C (p.Gly238Ala) in the TBX5 gene in a patient with a mild Holt–Oram syndrome phenotype (thoracic spine deformity (scoliosis) and scapula dysplasia and showing signs of mitral and triсuspid valve insufficiency with first- and second-degree regurgitation and atrial septal thinning) and life-threatening tachyarrhythmias that required a cardioverter-defibrillator implantation (CDI). The mutation is localized in the “hot spot” of the TBX5 gene. Evaluation of its pathogenicity by in silico analysis showed that the c.713G>C nucleotide substitution can lead to changes in the protein structure and/or its function. Non-sustained ventricular tachycardia/ventricular fibrillation, which is not characteristic of HOS, could have resulted from two additional rare substitutions (MAF < 0.01%): p.Val3634Asp, rs66785829 in the ANK2 gene and p.Arg1193Gln, rs41261344 in the SCN5A gene. Mutations in these genes affect the voltage-gated sodium channel functioning and cause hereditary arrhythmia.