RT Journal Article
SR Electronic
T1 Reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 130203
DO 10.1101/130203
A1 Lisa M. Neupert
A1 Michael Nothnagel
A1 Patrick May
A1 Aarno Palotie
A1 Mark Daly
A1 Peter Nürnberg
A1 Ingmar Blümcke
A1 Dennis Lal
YR 2017
UL http://biorxiv.org/content/early/2017/04/24/130203.abstract
AB Purpose Increasing availability of surgically resected brain tissue from Focal Cortical Dysplasia and low-grade epilepsy-associated tumor patients fostered large-scale genetic examination. However, assessment of germline and somatic variant pathogenicity remains difficult.Methods Here, we critically reevaluated the pathogenicity for all neuropathology-associated variants reported to date in the PubMed and ClinVar databases, including 12 disease-related genes and 88 neuropathology-associated missense variants. We (1) assessed evolutionary gene constraint using the pLI and missense z scores, (2) applied guidelines by the American College of Medical Genetics and Genomics (ACMG), and (3) predicted pathogenicity by using PolyPhen-2, CADD, and GERP.Results Constraint analysis classified only seven out of 12 genes to be likely disease-associated, while 35 (40%) of those 88 variants were classified as being variants of unknown significance (VUS) and 53 (60%) as being likely pathogenic (LPII). Pathogenicity prediction yielded discrimination between neuropathology-associated variants (LPII and VUS) and rare variant scores obtained from individuals present in the Genome Aggregation Database (gnomAD).Conclusion We conclude that several VUS are likely disease-associated and will be reclassified by future molecular evidence. In summary, interpretation of lesion-associated gene variants remains complex while the application of current ACMG guidelines including bioinformatic pathogenicity prediction will help improving interpretation and prediction.