{"id":18678,"date":"2025-12-03T14:36:26","date_gmt":"2025-12-03T12:36:26","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=18678"},"modified":"2025-12-03T14:36:26","modified_gmt":"2025-12-03T12:36:26","slug":"2025-automated-patch-clamp-data-improve-variant-classification-and-penetrance-stratification-for-scn5a-brugada-syndrome","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2025-automated-patch-clamp-data-improve-variant-classification-and-penetrance-stratification-for-scn5a-brugada-syndrome\/","title":{"rendered":"2025 &#8211; Automated patch clamp data improve variant classification and penetrance stratification for SCN5A\u2013Brugada syndrome"},"content":{"rendered":"<div class=\" sec\">\n<div class=\"title\">Background and Aims<\/div>\n<p class=\"chapter-para\">Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in\u00a0<em>SCN5A<\/em>, which encodes the cardiac sodium channel Na<sub>V<\/sub>1.5. Genetic workup of BrS is often complicated by\u00a0<em>SCN5A<\/em>\u00a0variants of uncertain significance (VUS) and\/or incomplete penetrance. This study deployed an\u00a0<em>SCN5A<\/em>-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine.<\/p>\n<\/div>\n<div class=\" sec\">\n<div class=\"title\">Methods<\/div>\n<p class=\"chapter-para\">All 252 missense and in-frame insertion\/deletion\u00a0<em>SCN5A<\/em>\u00a0variants from a previously published large cohort of BrS cases (<em>n<\/em>\u00a0= 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional\u00a0<em>Z<\/em>-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case\u2013control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD.<\/p>\n<\/div>\n<div class=\" sec\">\n<div class=\"title\">Results<\/div>\n<p class=\"chapter-para\">Most variants (146\/252) were functionally abnormal (<em>Z<\/em>\u00a0\u2264 \u22122), with 100 having severe loss-of-function (<em>Z<\/em>\u00a0\u2264 \u22124). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign.\u00a0<em>SCN5A<\/em>\u00a0variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore.\u00a0<em>SCN5A<\/em>\u00a0variant penetrance was proportional to the severity of loss-of-function; variants with Z \u2264 \u22126 had penetrance of 24.5% (15.9%\u201337.7% CI) and an odds ratio of 501 for BrS.<\/p>\n<\/div>\n<div class=\" sec\">\n<div class=\"title\">Conclusions<\/div>\n<p class=\"chapter-para\">This cohort-scale APC dataset stratifies\u00a0<em>SCN5A<\/em>\u00a0variants found in BrS patients into normal function \u2018bystander\u2019 variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the\u00a0<em>SCN5A<\/em>\u2013BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.<\/p>\n<\/div>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[53,76],"therapeutic_areas":[143],"target_categories":[61],"target_families":[332],"targets":[93],"resource_keyword":[],"class_list":["post-18678","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-assay-development-and-validation","application_areas-drug-discovery","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels","target_families-nav-channels","targets-nav1-5"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/18678","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=18678"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=18678"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=18678"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=18678"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=18678"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=18678"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=18678"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=18678"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=18678"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}