Person: Pérez Palma, Eduardo
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Pérez Palma
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Eduardo
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Eduardo Esteban Pérez Palma
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Publication CNV-ClinViewer: enhancing the clinical interpretation oflarge copy-number variants online(2023) Macnee, Marie; Pérez Palma, Eduardo; Brünger, Tobias; Klöckner, Chiara; Platzer, Konrad; Stefansk, Arthur; Montanucci, Ludovica; Bayat, Allan; Radtke, Maximilian; Collins, Ryan; Talkowski, Michael; Blankenberg, Daniel; Møller, Rikke; Lemke, Johannes; Nothnagel, Michael; May, Patrick; Lal, DennisMotivation: 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.Publication Quantitative Phenotype Morbidity Description of SATB2 - Associated Syndrome(2023) Zarate, Yuri; Bosanko, Katherine; Kannan, Amrit; Thomason, Ashlen; Nutt, Beth; Kumar, Nihit; Simmons, Kirt; Hiegert, Aaron; Hartzell, Larry; Johnson, Adam; Prater, Tabitha; Pérez Palma, Eduardo; Brünger, Tobias; Stefanski, Arthur; Lal, Dennis; Caffrey, AislingCharacterized by developmental delay with severe speech delay, dental anomalies, cleft palate, skeletal abnormalities, and behavioral difficulties, SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2. The SAS phenotype range of severity has been documented previously in large series. Using data from the SAS registry, we present the SAS severity score, a comprehensive scoring rubric that encompasses 15 different individual neurodevelopmental and systemic features. Higher (more severe) systemic and total (sum of neurodevelopmental and systemic scores) scores were seen for null variants located after amino acid 350 (the start of the CUT1 domain), the recurrent missense Arg389Cys variant (n=10), intragenic deletions, and larger chromosomal deletions. The Arg389Cys variant had the highest cognitive, verbal, and sialorrhea severity scores, while large chromosomal deletions had the highest expressive, ambulation, palate, feeding and growth, neurodevelopmental, and total scores. Missense variants not located in the CUT1 or CUT2 domain scored lower in several subcategories. We conclude that the SAS severity score allows quantitative phenotype morbidity description that can be used in routine clinical counseling. Further refinement and validation of the SAS severity score are expected over time. All data from this project can be interactively explored in a new portal.Publication SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis(2023) Stefanski, Arthur; Pérez Palma, Eduardo; Brünger, Tobias; Montanucci, Ludovica; Gati, Cornelius; Klöckner, Chiara; Johannesen, Katrine; Goodspeed, Kimberly; Macnee, Marie; Deng, Alexander; Aledo, Ángel; Borovikov,Artem; Kava, Maina; Bouman, Arjan; Hajianpour, M.; Pal, Deb; Engelen, Marc; Hagebeuk, Eveline; Shinawi, Marwan; Heidlebaugh, Alexis; Oetjens, Kathryn; Hoffman, Trevor; Striano, Pasquale; Freed, Amanda; Futtrup, Line; Balslev, Thomas; Abulí, Anna; Danvoye, Leslie; Lederer, Damien; Balci, Tugce; Nabavi, Maryam; Butler, Elizabeth; Drewes, Sarah; Van Engelen, Kalene; Howell, Katherine; Khoury, Jean; May, Patrick; Trinidad, Marena; Froelich, Steven; Lemke, JohannesGenetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).Publication Editorial: SLC6A1: the past, present and future(2023) Johannesen, Katrine M.; Pérez Palma, Eduardo; Rubboli, GuidoPublication 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 Molecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of four SCN2A variants(2024) Bhattarai, Nisha; Montanucci, Ludovica; Brünger, Tobias; Pérez Palma, Eduardo; Martin, William; Smith, Iris; Eng, Charis; Cheng, Feixiong; Helbig, Ingo; Müller, Rikke; Brunklaus, Andreas; Schorge, Stephanie; Lal, DennisSCN2A gene disorders cover a wide range of medical conditions, from epileptic encephalopathies to neurodevelopmental disorders. The variants of these disorders, studied through electrophysiology, show complex behaviors that go beyond simple classification as either gain or loss of function. In our study, we simulated the biophysical effects of variants (R937C, V208E, S1336Y, and R853Q) to understand their impact. Our findings reveal that all these variants negatively affect the structural stability of the gene, with R937C being the most unstable. Specifically, R937C disrupts important charged interactions affecting sodium ion flow, while S1336Y introduces a new interaction that impacts the channel’s inactivation gate. Conversely, the variants V208E and R853Q, which are located in the voltage-sensing domains, have opposite effects: R853Q increases compactness and interaction, whereas V208E shows a decrease. Our computer-based method offers a scalable way to gain crucial insights into how genetic variants influence channel dysfunction and contribute to neurodevelopmental disorders.Publication Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies(2024) Gallagher, Declan; Pérez; Pérez Palma, Eduardo; Bruenger, Tobias; Ghanty, Ismael; Brilstra, Eva; Ceulemans, Berten; Chemaly, Nicole; De Lange, Iris; Depienne, Christel; Guerrini, Renzo; Mei, Davide; Møller, Rikke; Nabbout, Rima; Regan, Brigid; Schneider, Amy; Scheffer, Ingrid; Schoonjans, An; Symonds, Joseph; Weckhuysen, Sarah; Zuber, Sameer; Lal, Dennis; Brunklaus, AndreasObjective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood. Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. Significance: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS