Browsing by Author "Stefanski, Arthur"
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Publication Identification and quantification of oligogenic loss-of-function disorders(2021) Stefanski, Arthur; Pérez, Eduardo; Mrdjen, Marko; McHugh, Megan; Leu, Costin; Lal, DennisPurpose: Monogenic disorders can present clinically heterogeneous symptoms. We hypothesized that in patients with a monogenic disorder caused by a large deletion, frequently additional loss-of-function (LOF)-intolerant genes are affected, potentially contributing to the phenotype. Methods: We investigated the LOF-intolerant gene distribution across the genome and its association with benign population and pathogenic classified deletions from individuals with presumably monogenic disorders. For people with presumably monogenic epilepsy, we compared Human Phenotype Ontology terms in people with large and small deletions. Results: We identified LOF-intolerant gene dense regions that were enriched for ClinVar and depleted for population copy number variants. Analysis of data from >143,000 individuals with a suspected monogenic disorder showed that 2.5% of haploinsufficiency disorder-associated deletions can affect at least 1 other LOF-intolerant gene. Focusing on epilepsy, we observed that 13.1% of pathogenic and likely pathogenic ClinVar deletions <3 megabase pair, covering the diagnostically most relevant genes, affected at least 1 additional LOF-intolerant gene. Those patients have potentially more complex phenotypes with increasing deletion size. Conclusion: We could systematically show that large deletions frequently affected admditional LOF-intolerant genes in addition to the established disease gene. Further research is needed to understand how additional potential disease-relevant genes influence monogenic disorders to improve clinical care and the efficacy of targeted therapies.Publication Incidence and prevalence of major epilepsy-associated brain lesions(2022) López; Javier; Smuk, Victoria; Leu, Costin; Nasr, Gaelle; Vegh, Deborah; Stefanski, Arthur; Pérez, Eduardo; Busch, Robyn; Jehi, Lara; Najm, Imad; Blümcke, Ingmar; Lal, DennisEpilepsy surgery is an effective treatment option for drug-resistant focal epilepsy patients with associated structural brain lesions. However, little epidemiological data are available regarding the number of patients with these lesions. We reviewed data regarding (1) the prevalence and incidence of epilepsy; (2) the proportion of epilepsy patients with focal epilepsy, drug-resistant epilepsy, and drug-resistant focal epilepsies; and (3) the number of epilepsy presurgical evaluations and surgical resections. We also assessed the relative proportion of brain lesions using post-surgical histopathological findings from 541 surgical patients from the Cleveland Clinic and 9,523 patients from a European multi-center cohort. Data were combined to generate surgical candidate incidence and prevalence estimates and the first lesion-specific estimates for hippocampal sclerosis (HS), low-grade epilepsy-associated brain tumors (LEAT), malformations of cortical development (MCD), glial scars, vascular malformations, and encephalitis. The most frequently diagnosed brain lesions were HS (incidence = 2.32 ± 0.26 in 100,000, prevalence = 19.40 ± 2.16 in 100,000) for adults and MCD (incidence = 1.15 ± 0.34 in 100,000, prevalence = 6.52 ± 1.89 in 100,000) for children. Our estimates can guide patient advocacy groups, clinicians, researchers, policymakers in education, development of health care strategy, resource allocation, and reimbursement schedules.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/).