RESUMEN
Variants in Tbox transcription factor 5 (TBX5) can result in a wide phenotypic spectrum, specifically in the heart and the limbs. TBX5 has been implicated in causing nonsyndromic cardiac defects and HoltOram syndrome (HOS). The present study investigated the underlying molecular etiology of a family with heterogeneous heart defects. The proband had mixedtype total anomalous pulmonary venous return (mixedtype TAPVR), whereas her mother had an atrial septal defect. Genetic testing through triobased wholeexome sequencing was used to reveal the molecular etiology. A nonsense variant was identified in TBX5 (c.577G>T; p.Gly193*) initially showing cosegregation with a presumably nonsyndromic presentation of congenital heart disease. Subsequent genetic investigations and more complete phenotyping led to the correct diagnosis of HOS, documenting the novel association of mixedtype TAPVR with HOS. Finally, protein modeling of the mutant TBX5 protein that harbored this pathogenic nonsense variant (p.Gly193*) revealed a substantial drop in the quantity of noncovalent bonds. The decrease in the number of noncovalent bonds suggested that the resultant mutant dimer was less stable compared with the wildtype protein, consequently affecting the protein's ability to bind DNA. The present findings extended the phenotypic cardiac defects associated with HOS; to the best of our knowledge, this is the first association of mixedtype TAPVR with TBX5. Prior to the current analysis, the molecular association of TAPVR with HOS had never been documented; hence, this is the first genetic investigation to report the association between TAPVR and HOS. Furthermore, it was demonstrated that the nullvariants reported in the Tbox domain of TBX5 were associated with a wide range of cardiac and/or skeletal anomalies on both the interand intrafamilial levels. In conclusion, genetic testing was highlighted as a potentially powerful approach in the prognostication of the proper diagnosis.