A novel desmoplakin dominant mutation responsible for Carvajal/Naxos syndrome identified by exome sequencing

Abstract

Purpose: Naxos and Carvajal syndrome are rare forms of recessive Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), characterized by ventricle dysplasia/dilated cardiomyopathy and ventricular arrhythmias, associated with palmoplantar keratoderma and woolly hair. We report the case of an Italian 37-year-old woman with a form of ARVC characterized by phenotypic features overlapping Naxos/Carvajal syndrome, with a dominant model of inheritance. Whole Exome Sequencing (WES) allowed the identification of a novel mutation in the desmoplakin gene (DSP), which was previously missed by traditional Sanger sequencing. Methods: The woman was admitted to the hospital after resuscitated cardiac arrest. Clinical and instrumental evaluations showed mild biventricular systolic dysfunction, with dilated ventricles and areas of bulging in the lateral wall of the right ventricle. She also had palmoplantar keratoderma and family history of juvenile sudden cardiac death (brother, 28 year-old). Traditional Sanger sequencing failed to identify any mutations in the genes usually associated with ARVC (transforming growth factor beta-3, ryanodine receptor 2, desmoplakin, plakophilin-2, desmoglein-2, desmocollin-2 transmembrane protein 43, junction plakoglobin protein). WES was therefore performed on the Illumina HiScan SQ platform. After bioinformatics analysis, data were filtered by frequency, function, conservation scores and predicted deleteriousness by means in silico 3D modeling. Prioritization of variants was performed by Gene Prioritization Portal and then cosegregation was tested in the family. Results: Family's pedigree showed a dominant model of inheritance. 65993 variants were individuated by bioinformatics analysis; after data filtering and integration of filtered results with patient's clinical features, 4 potential mutations were selected. Only two of those variants cosegregated with the disease in the family: c.878A>T, p.Glu293Val in the DSP gene and c.626A>C, p.Tyr209Ser in the cytochrome c oxidase assembly gene (SCO2). Since the cardiomyopathy related to SCO2 gene mutations is usually associated with encephalopathy and is fatal in children, we excluded the causative role of such gene in our family. Therefore, we considered the DSP-Glu293Val variant as disease-causing and we hypothesized a modifier role for the SCO2 variant. Conclusions: We identified a novel DSP gene variant associated to a rare dominant form of Carvajal/Naxos syndrome, by Whole Exome Sequencing. Our study confirmed the high efficiency of NGS, both in terms of accuracy and sensitivity, when compared to traditional sequencing.