Fig. 1: A NAA10 variant is associated with clinical long QT syndrome and severe cardiomyopathy.

a A four-generation family pedigree identified predominantly male patients with QT prolongation, developmental delay, and early mortality in a family referred for “gene-negative long QT syndrome”. Clinical sequencing revealed that the NAA10 p.R4S variant (red) to segregate with the clinical phenotype, whereas the variant of unknown significance in KCNH2 (p.R164H, shown in green) did not segregate with QT prolongation. In generation III, both male subjects (III:9, III:11) died as infants. A female (III:6) died at the age of 26 years from cardiac arrest prior to the availability of testing for NAA10. b Sanger sequencing of the proband (III:8). c ECG for patient III:8 with QT prolongation (QTc = 545 msec) and inverted T-waves. d A schematic of the exon structure of the NAA10 gene overlaid with the p.R4S variant and its relationship to the domain structure of the NAA10 protein. e Tracing from an implantable cardiac defibrillator showing short-long-short coupling prior to initiation of Torsades de Pointes (TdP). f M-mode echocardiography of patient III:8 showing a calculated ejection fraction (EF) of 22.3%. g Cardiac micrographs from patient III:8 post-mortem. The upper panel shows Masson’s Trichrome staining (scale bar: 100 µm), and the lower panel shows hematoxylin and eosin staining (scale bar: 50 µm) of the left ventricle. Arrowheads indicate abnormal appearing nuclei. Abbreviations for panel A: CM Cardiomyopathy, d. age of death, Myo Peripheral skeletal myopathy, NDD Neurodevelopmental delay, ↑QT QTc prolongation, SCD Sudden cardiac death, and VT Recurrent ventricular tachycardia.