Delineation of functionally essential protein regions for 242 neurodevelopmental genes

Iqbal, S., Brünger, T., Pérez-Palma, E., Macnee, M., Brunklaus, A., Daly, M. J., Campbell, A. J., Hoksza, D., May, P. and Lal, D. (2022) Delineation of functionally essential protein regions for 242 neurodevelopmental genes. Brain, (doi: 10.1093/brain/awac381) (PMID:36256779) (Early Online Publication)

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Neurodevelopmental disorders (NDDs), including severe pediatric epilepsy, autism, and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘Variants of Uncertain Significance’. To safely enroll patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the three-dimensional (3D) structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14,377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including >360,000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients. In summary, we developed a comprehensive protein structure set for 242 neurodevelopmental disorders and identified 14,377 Essential3D sites in these. All data are available at for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.

Item Type:Articles
Additional Information:This work was supported by the National Institute of Health (grants: NIH 5U54NS108874, 1R01NS112499-01A1), the Center Without Walls on ion channel function in epilepsy ("Channelopathy-associated Research Center", grant U54 NS108874) and Dravet Syndrome Foundation research grant to D.L., the Fonds Nationale de la Recherche in Luxembourg Research Unit FOR-2715, FNR grant INTER/DFG/21/16394868 MechEPI2) to P.M. and theFederal Ministry for Education and Research (BMBF, Treat-ION, 01GM1907D) to D.L., T.B. and P.M. P.M. was supported by Treat-Ion2 BMBF 01GM2210B.
Status:Early Online Publication
Glasgow Author(s) Enlighten ID:Brunklaus, Professor Andreas
Authors: Iqbal, S., Brünger, T., Pérez-Palma, E., Macnee, M., Brunklaus, A., Daly, M. J., Campbell, A. J., Hoksza, D., May, P., and Lal, D.
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
Journal Name:Brain
Publisher:Oxford University Press
ISSN (Online):1460-2156
Published Online:18 October 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Brain 2022
Publisher Policy:Reproduced under a Creative Commons License

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