Universität zu Köln

Iqbal, Sumaiya ORCID: 0000-0001-7700-4374, Bruenger, Tobias, Perez-Palma, Eduardo, Macnee, Marie, Brunklaus, Andreas ORCID: 0000-0002-7728-6903, Daly, Mark J., Campbell, Arthur J., Hoksza, David ORCID: 0000-0003-4679-0557, May, Patrick ORCID: 0000-0001-8698-3770 and Lal, Dennis (2023). Delineation of functionally essential protein regions for 242 neurodevelopmental genes. Brain, 146 (2). S. 519 - 534. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

Neurodevelopmental disorders (NDDs), including severe paediatric 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 enrol 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 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 NDDs and identified 14377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org 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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Iqbal, Sumaiya UNSPECIFIED orcid.org/0000-0001-7700-4374 UNSPECIFIED Bruenger, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Perez-Palma, Eduardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Macnee, Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunklaus, Andreas UNSPECIFIED orcid.org/0000-0002-7728-6903 UNSPECIFIED Daly, Mark J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Campbell, Arthur J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoksza, David UNSPECIFIED orcid.org/0000-0003-4679-0557 UNSPECIFIED May, Patrick UNSPECIFIED orcid.org/0000-0001-8698-3770 UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-691893
DOI:	10.1093/brain/awac381
Journal or Publication Title:	Brain
Volume:	146
Number:	2
Page Range:	S. 519 - 534
Date:	2023
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VARIANTS; MUTATIONS; PREDICTION; DISORDERS; MEDICINE; GENETICS; EPILEPSY; BIOLOGY; RISK Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69189