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Project Title
Genética en Epilepsia: Caracterización de variantes genéticas raras y comunes en pacientes Chilenos con epilepsias y encefalopatías epilépticas del desarrollo
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PAI77200124
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Start Date
2020

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Publication

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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CNV-ClinViewer: enhancing the clinical interpretation of large copy-number variants online

2023 , Marie Macnee , Eduardo Pérez-Palma , Tobias Brünger , Chiara Klöckner , Konrad Platzer , Arthur Stefanski , Ludovica Montanucci , Allan Bayat , Maximilian Radtke , Ryan L Collins , Michael Talkowski , Daniel Blankenberg , Rikke S Møller , Johannes R Lemke , Michael Nothnagel , Patrick May , Dennis Lal , Christina Kendziorski

Abstract Motivation Pathogenic copy-number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype–phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts. Results Here, we introduce the CNV-ClinViewer, an open-source web application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment, the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators’ patient care and for basic scientists’ translational genomic research. Availability and implementation The web application is freely available at https://cnv-ClinViewer.broadinstitute.org and the open-source code can be found at https://github.com/LalResearchGroup/CNV-clinviewer.

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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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