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<i>SLC6A1</i> variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis
(2023)
Arthur Stefanski
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Eduardo Pérez-Palma
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Tobias Brünger
;
Ludovica Montanucci
;
Cornelius Gati
<jats:title>Abstract</jats:title> <jats:p>Genetic 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.</jats:p> <jats:p>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.</jats:p> <jats:p>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).</jats:p> <jats:p>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/).</jats:p>
Scopus© Citations 3 3
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Quantitative Phenotype Morbidity Description of SATB2-Associated Syndrome
(2023)
Yuri A. Zarate
;
Katherine Bosanko
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Amrit Kannan
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Ashlen Thomason
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Beth Nutt
<jats:p>Characterized 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 (<jats:inline-formula> <math xmlns="http://www.w3.org/1998/Math/MathML" id="M1"> <mi>n</mi> <mo>=</mo> <mn>10</mn> </math> </jats:inline-formula>), 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.</jats:p>
Scopus© Citations 5 7
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CNV-ClinViewer: enhancing the clinical interpretation of large copy-number variants online
(2023)
Marie Macnee
;
Eduardo Pérez-Palma
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Tobias Brünger
;
Chiara Klöckner
;
Konrad Platzer
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Motivation</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Availability and implementation</jats:title> <jats:p>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.</jats:p> </jats:sec>
Scopus© Citations 13 15
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Identification and quantification of oligogenic loss-of-function disorders
(2022)
Arthur Stefanski
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Eduardo Pérez-Palma
;
Marko Mrdjen
;
Megan McHugh
;
Costin Leu
Scopus© Citations 3 1
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Incidence and prevalence of major epilepsy-associated brain lesions
(2022)
Javier A. López-Rivera
;
Victoria Smuk
;
Costin Leu
;
Gaelle Nasr
;
Deborah Vegh
Scopus© Citations 15 1

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