C.O.5 Ventricular noncompaction with arthrogryposis due to TTN compound heterozygosity leading to loss of functional TTN kinase domain

Abstract Arthrogryposis is a relatively common disorder characterized by multiple joint contractures with considerable clinical and genetical heterogeneity. Left ventricular non compaction syndrome (LVNC) is a congenital heart defect, usually classified as a form of dilated cardiomyopathy, defined by prominent left-ventricular trabeculae and deep intertrabecular recesses due to an abnormal compaction of the cardiac tissue during embryogenesis. Although mutations of sarcomere proteins have been separately reported in each of these disorders, no condition associating both phenotypes is known. Here we describe the case report of a girl from non consanguineous caucasian family presenting with a novel phenotype associating congenital core myopathy, arthrogryposis and LVNC. Using candidate gene analysis followed by targeted exome sequencing in this patient we identified two novel compound heterozygous mutations of the titin gene TTN . A maternal splicing mutation predicted to generate a truncated protein; a paternal missense mutation in the kinase domain resulting in total loss of kinase function. Both heterozygous parents were perfectly healthy, indicating that not all TTN nonsense mutations cause disease at heterozygous state. In summary, we describe here a novel condition combining arthrogryposis and LVNC and show that it is caused by compound heterozygous mutations of TTN leading for the first time to an absence of a functional kinase domain in humans. These findings not only enlarge the mutational and phenotypical spectrum of titinopathies to include antenatal-onset conditions and LVNC, but also suggest that the kinase domain of titin might be indispensable for normal cardiac morphogenesis.