An Approach to Successful Development of Clinician-Scientists in Neurology: The NINDS R25 Experience.

Objective: Training clinician-scientists is a primary objective of many academic neurology departments, as these individuals are uniquely positioned to perform insightful clinical or laboratory-based research informed both by clinical knowledge and their own experiences caring for patients. Despite its importance, training clinician-scientists has perhaps never been so challenging. The National Institute of Neurologic Disorders and Stroke (NINDS) R25 program was designed in an attempt to support these individuals, decrease the time needed to obtain National Institutes of Health K awards, and to help educate a cohort of trainees preparing for a career in academic neurology.

WNT signalling control by KDM5C during development affects cognition.

Although KDM5C is one of the most frequently mutated genes in X-linked intellectual disability, the exact mechanisms that lead to cognitive impairment remain unknown. Here we use human patient-derived induced pluripotent stem cells and Kdm5c knockout mice to conduct cellular, transcriptomic, chromatin and behavioural studies. KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability.

Developmental basis of SHH medulloblastoma heterogeneity.

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development.

Clinical variants paired with phenotype: A rich resource for brain gene curation.

Purpose: Clinically ascertained variants are under-utilized in neurodevelopmental disorder research. We established the Brain Gene Registry (BGR) to coregister clinically identified variants in putative brain genes with participant phenotypes. Here, we report 179 genetic variants in the first 179 BGR registrants and analyze the proportion that were novel to ClinVar at the time of entry and those that were absent in other disease databases.

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma.

Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis.