De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies.

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.

An Objective Method for Evaluating Next-Generation Sequencing Panels.

PURPOSE: Next-generation sequencing panels are particularly useful in identifying genetic diagnoses in patients with nonspecific clinical findings by allowing for analysis of many genes at once. The purpose of this study was to develop a simple, objective system to evaluate the quality of available next-generation sequencing panels. METHODS: A list of potentially important features of next-generation sequencing panels generated from the literature was evaluated for accessibility and objectivity and distilled to a "core" set of quality features. This was then applied to a clinical setting using the example of epilepsy panels. Panels at 8 laboratories were rated based on several objective measures to create a scoring system that differentiated between labs in a clinically meaningful way. RESULTS: There was substantial variability in 6 "core" test criteria, allowing for creation of a scoring system that clearly distinguished labs based on identified strengths and weaknesses of each panel. CONCLUSION: We have demonstrated an objective method for comparing next-generation sequencing panels that can be applied or adapted to any clinical phenotype for which genetic testing is available. This method offers an unbiased approach to determining the ideal test for a given indication at a given time.