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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Internal ID
PAI77200124
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Start Date
2020
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Item type:Publication, Copy Number Variation Analysis from SNP Genotyping Microarrays in Large Cohorts of Neurological Disorders(2022); 1 2 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Structural mapping of GABRB3 variants reveals genotype–phenotype correlations(2022)Scopus© Citations 16 2 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Gene variant effects across sodium channelopathies predict function and guide precision therapy(2022); Henrike Heyne<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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 &lt; 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 &lt; 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 &lt; 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects.</jats:p> <jats:p>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).</jats:p>3 1Scopus© Citations 63 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, CNV-ClinViewer: enhancing the clinical interpretation of large copy-number variants online(2023)Scopus© Citations 13 15