PEREZ PALMA, EDUARDO ESTEBAN
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PEREZ PALMA, EDUARDO ESTEBAN
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eduardoperez@udd.cl
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55981322300

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2024 2024 2023 2023 2022 2022 2021 2021 0.0 0.0 1.0 1.0 2.0 2.0 3.0 3.0 4.0 4.0 5.0 5.0 6.0 6.0 7.0 7.0

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Structural mapping of GABRB3 variants reveals genotype–phenotype correlations

2022 , Katrine M. Johannesen , Sumaiya Iqbal , Milena Guazzi , Nazanin A. Mohammadi , PEREZ PALMA, EDUARDO ESTEBAN , Elise Schaefer , Anne De Saint Martin , Marie Therese Abiwarde , Amy McTague , Roser Pons , Amelie Piton , Manju A. Kurian , Gautam Ambegaonkar , Helen Firth , Alba Sanchis-Juan , Marie Deprez , Katrien Jansen , Liesbeth De Waele , Eva H. Briltra , Nienke E. Verbeek , Marjan van Kempen , Walid Fazeli , Pasquale Striano , Federico Zara , Gerhard Visser , Hilde M.H. Braakman , Martin Haeusler , Miriam Elbracht , Ulvi Vaher , Thomas Smol , Johannes R. Lemke , Konrad Platzer , Joanna Kennedy , Karl Martin Klein , Ping Yee Billie Au , Kimberly Smyth , Julie Kaplan , Morgan Thomas , Malin K. Dewenter , Argirios Dinopoulos , Arthur J. Campbell , Dennis Lal , Damien Lederer , Vivian W.Y. Liao , Philip K. Ahring , Rikke S. Møller , Elena Gardella

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Copy Number Variation Analysis from SNP Genotyping Microarrays in Large Cohorts of Neurological Disorders

2022 , PEREZ PALMA, EDUARDO ESTEBAN , Lisa-Marie Niestroj , Miguel Inca-Martínez , Camilo Villaman , Dennis Lal , Ignacio Mata

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Gene variant effects across sodium channelopathies predict function and guide precision therapy

2022 , Andreas Brunklaus , Tony Feng , Tobias Brünger , PEREZ PALMA, EDUARDO ESTEBAN , Henrike Heyne , Emma Matthews , Christopher Semsarian , Joseph D Symonds , Sameer M Zuberi , Dennis Lal , Stephanie Schorge

Abstract Pathogenic variants in the voltage-gated sodium channel gene family lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes, we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterized in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. Thirty-five out of 38 of those pairs resulted in similar functional consequences, indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% confidence interval = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non-conserved domains (odds ratio = 18.6; 95% confidence interval = 10.9–34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function variants, whereas inactivation sites were associated with gain-of-function (odds ratio = 42.1, 95% confidence interval = 14.5–122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first gain- versus loss-of-function topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org).

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Data-driven historical characterization of epilepsy-associated genes

2023 , Marie Macnee , PEREZ PALMA, EDUARDO ESTEBAN , Javier A. López-Rivera , Alina Ivaniuk , Patrick May , Rikke S. Møller , Dennis Lal

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Genomic analysis of AlphaFold2-predicted structures identifies maps of 3D essential sites in 243 neurodevelopmental disorder-associated proteins

2022 , Sumaiya Iqbal , Tobias Brünger , PEREZ PALMA, EDUARDO ESTEBAN , David Hoksza , Arthur J. Campbell , Mark J. Daly , Patrick May , Dennis Lal

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GRIN Portal: An Interactive Web Application Exploring GRIN Genes and Related Disorders

2023 , PEREZ PALMA, EDUARDO ESTEBAN , Kloeckner, Chiara , Bruenger, Tobias , Krey, Ilona , Macnee, Marie , Myers, Scott J , Yuan, Hongjie , Arthur Stefanski , May, Patrick , Sargent, Jenifer , Kristen Park , Ramsey, Amy J. , Benke, Tim , Traynelis, Stephen F , Dennis Lal , Johannes Lemke

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The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

2022 , Javier A López-Rivera , Costin Leu , Marie Macnee , Jean Khoury , Lucas Hoffmann , Roland Coras , Katja Kobow , Nisha Bhattarai , PEREZ PALMA, EDUARDO ESTEBAN , Hajo Hamer , Sebastian Brandner , Karl Rössler , Christian G Bien , Thilo Kalbhenn , Tom Pieper , Till Hartlieb , Elizabeth Butler , Giulio Genovese , Kerstin Becker , Janine Altmüller , Lisa-Marie Niestroj , Lisa Ferguson , Robyn M Busch , Peter Nürnberg , Imad Najm , Ingmar Blümcke , Dennis Lal

Abstract Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed ‘second hit’ disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21–q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.

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Molecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of four SCN2A variants

2024 , PEREZ PALMA, EDUARDO ESTEBAN , Nisha Bhattarai , Ludovica Montanucci , Bruenger, Tobias , Martin, William , Smith, Iris N. , Cheng, Feixiong , Charis Eng , Helbig, Ingo , Moller, Rikkie S , Andreas Brunklaus , Stephanie Schorge , Dennis Lal

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Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes

2022 , Tobias Brünger , PEREZ PALMA, EDUARDO ESTEBAN , Ludovica Montanucci , Michael Nothnagel , Rikke S Møller , Stephanie Schorge , Sameer Zuberi , Joseph Symonds , Johannes R Lemke , Andreas Brunklaus , Stephen F Traynelis , Patrick May , Dennis Lal

Abstract Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion-channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated. We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion-channel families. We collected and curated 3049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12 546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures. We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis centre and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1422 neurodevelopmental disorder pathogenic patient variants and 679 electrophysiological experiments, we show that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain versus loss-of-channel function. In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional readouts and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.

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SimText: a text mining framework for interactive analysis and visualization of similarities among biomedical entities

2021 , Marie Macnee , PEREZ PALMA, EDUARDO ESTEBAN , Sarah Schumacher-Bass , Jarrod Dalton , Costin Leu , Daniel Blankenberg , Dennis Lal , Jonathan Wren

Abstract Summary Literature exploration in PubMed on a large number of biomedical entities (e.g. genes, diseases or experiments) can be time-consuming and challenging, especially when assessing associations between entities. Here, we describe SimText, a user-friendly toolset that provides customizable and systematic workflows for the analysis of similarities among a set of entities based on text. SimText can be used for (i) text collection from PubMed and extraction of words with different text mining approaches, and (ii) interactive analysis and visualization of data using unsupervised learning techniques in an interactive app. Availability and implementation We developed SimText as an open-source R software and integrated it into Galaxy (https://usegalaxy.eu), an online data analysis platform with supporting self-learning training material available at https://training.galaxyproject.org. A command-line version of the toolset is available for download from GitHub (https://github.com/dlal-group/simtext) or as Docker image (https://hub.docker.com/r/dlalgroup/simtext/tags.). Supplementary information Supplementary data are available at Bioinformatics online.

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