ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Epilepsy panel testing criteria: A clinical assessment.

Epilepsy is a common, and often genetic, neurological disorder. Few guidelines exist to help medical providers or insurance companies decide when to order or cover epilepsy panels for patients with epilepsy. The most recent guidelines were published by NSGC after this study's data collection. Since 2017, the Genetic Testing Stewardship Program (GTSP) at UPMC Children's Hospital of Pittsburgh (CHP) has been utilizing a set of internally developed epilepsy panel (EP) testing criteria to facilitate appropriate EP ordering practices. The purpose of this study was to assess these testing criteria by determining their sensitivities and positive predictive values (PPV). Retrospective chart review of the electronic medical record (EMR) was performed for 1242 CHP Neurology patients that were evaluated for a primary diagnosis of epilepsy between 2016 and 2018. One hundred and nine patients had EPs at various testing laboratories. Of the patients that met criteria, 17 had diagnostic EPs and 54 had negative EPs. Criteria were organized into category groupings (C1-C4), and analyzed alone for C1, in pairs for C2, etc. The highest sensitivity and PPV results in each category grouping were: C1 (64.7%, 60%); C2, (88%, 30.3%); C3, (94.1%, 27.1%); C4, (94.1%, 25.4%). Family history was crucial to increasing sensitivity. Confidence intervals (CIs) narrowed as category grouping level increased, though this was not statistically significant due to the considerable CI overlap across category groupings. The PPV from C4 was applied to the untested population cohort and predicted 121 patients with unidentified positive EPs. This study presents data supporting the predictive capabilities of EP testing criteria and suggests the addition of a family history criterion. This study impacts public health by encouraging the adoption of evidence-driven insurance policies and by suggesting guidelines to ease EP ordering and coverage decisions, which could potentially improve patient access to EP testing.