{"id":13273,"date":"2023-12-07T14:17:01","date_gmt":"2023-12-07T14:17:01","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13273"},"modified":"2024-01-18T10:14:48","modified_gmt":"2024-01-18T10:14:48","slug":"2023-exome-sequencing-of-atp1a3-negative-cases-of-alternating-hemiplegia-of-childhood-reveals-scn2a-as-a-novel-causative-gene","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2023-exome-sequencing-of-atp1a3-negative-cases-of-alternating-hemiplegia-of-childhood-reveals-scn2a-as-a-novel-causative-gene\/","title":{"rendered":"2023 &#8211; Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene"},"content":{"rendered":"<p>Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in\u00a0<i>ATP1A3<\/i>\u00a0encoding the catalytic \u03b13 subunit of neuronal Na<sup>+\/<\/sup>K<sup>+<\/sup>\u00a0ATPases. The remainder of the patients are genetically unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26\u00a0<i>ATP1A3<\/i>-negative index patients with a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic, intronic, and flanking regions of\u00a0<i>ATP1A3<\/i>\u00a0in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing, we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including\u00a0<i>RHOBTB2<\/i>\u00a0(<i>n<\/i>\u2009=\u20093),\u00a0<i>ATP1A2<\/i>\u00a0(<i>n<\/i>\u2009=\u20093),\u00a0<i>ANK3<\/i>\u00a0(<i>n<\/i>\u2009=\u20091),\u00a0<i>SCN2A<\/i>\u00a0(<i>n<\/i>\u2009=\u20091), and\u00a0<i>CHD2<\/i>\u00a0(<i>n<\/i>\u2009=\u20091). In follow-up investigations, two additional\u00a0<i>ATP1A3<\/i>-negative individuals were found to have rare missense\u00a0<i>SCN2A<\/i>\u00a0variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance could not be determined. Functional evaluation of the variants identified in\u00a0<i>SCN2A<\/i>\u00a0and\u00a0<i>ATP1A2<\/i>\u00a0supports the pathogenicity of the identified variants. Our data show that genetic variants in various neurodevelopmental genes, including\u00a0<i>SCN2A<\/i>, lead to AHC or AHC-like presentation. Still, the majority of\u00a0<i>ATP1A3<\/i>-negative AHC or AHC-like patients remain unexplained, suggesting that other mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,76],"therapeutic_areas":[55],"target_categories":[61],"target_families":[332],"targets":[212],"resource_keyword":[],"class_list":["post-13273","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-drug-discovery","therapeutic_areas-cns","target_categories-voltage-gated-ion-channels","target_families-nav-channels","targets-nav1-2"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/13273","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=13273"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=13273"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=13273"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=13273"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=13273"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=13273"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=13273"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=13273"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=13273"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}