Browsing by Author "Campbell, Arthur"
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Publication Delineation of functionally essential protein regions for 242 neurodevelopmental genes(2022) Iqbal, Sumaiya; Brünger, Tobias; Pérez, Eduardo; Macnee, Marie; Brunklaus, Andreas; Daly, Mark; Campbell, Arthur; Hoksza, David; May, Patrick; Lal, DennisNeurodevelopmental 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 14 377 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.Publication Genomic analysis of AlphaFold2-predicted structures identifies maps of 3D essential sites in 243 neurodevelopmental disorder-associated proteins(2022) Iqbal, Sumaiya; Brunger, Tobias; Pérez Palma, Eduardo; Hoksza, David; Campbell, Arthur; Daly, Mark; May, Patrick; Lal, DennisWe propose a new methodology to identify maps of essential sites (i.e., amino acid residues) in 3D, called Essential 3D sites.Publication Structural mapping of GABRB3 variants reveals genotype-phenotype correlations(2021) Johannesen, Katrine; Iqba, Sumaiya; Guazz, Milena; Mohammadi, Nazanin; Pérez, Eduardo; Schaefer, Elise; De Saint Martin, Anne; Abiwarde, Marie; McTague, Amy; Pons, Roser; Piton, Amelie; Kurian, Manju; Ambegaonkar, Gautam; Firth, Helen; Sanchis, Alba; Deprez, Marie; Jansen, Katrien; De Waele, Liesbeth; Briltra, Eva; Verbeek, Nienke; Van Kempen, Marjan; Fazeli, Walid; Striano, Pasquale; Zara, Federico; Visser, Gerhard; Braakman, Hilde; Haeusle, Martin; Elbracht, Miriam; Vahe, Ulvi; Smol, Thomas; Lemke, Johannes; Platzer, Konrad; Kennedy, Joanna; Martin, Karl; Ping, Billie; Smyth, Kimberly; Kaplan, Julie; Thomas, Morgan; Dewenter, Malin; Dinopoulos, Argirios; Campbell, Arthur; Lal, Dennis; Lederer, Damien; Liao, Vivian; Ahring, Philip; Møller, Rikke; Gardella, ElenaPurpose: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. Results: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. Conclusion: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.