{"doi":"10.1101/2020.08.31.20184481","title":"Pathogenic <i>SPTBN1</i> variants cause a novel autosomal dominant neurodevelopmental syndrome","abstract":"Abstract SPTBN1 encodes βII-spectrin, the ubiquitously expressed member of the β-spectrin family that forms micrometer-scale networks associated with plasma membranes. βII-spectrin is abundantly expressed in the brain, where it is essential for neuronal development and connectivity. Mice deficient in neuronal βII-spectrin expression have defects in cortical organization, global developmental delay, dysmorphisms, and behavioral deficiencies of corresponding severity. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous variants in this gene may also present with measurable compromise of neural development and function. Here we report the identification of heterozygous SPTBN1 variants in 29 individuals who present with global developmental, language and motor delays, mild to severe intellectual disability, autistic features, seizures, behavioral and movement abnormalities, hypotonia, and variable dysmorphic facial features. We show that these SPTBN1 variants lead to loss-of-function, gain-of-function, and dominant negative effects that affect protein stability, disrupt binding to key protein partners, and disturb cytoskeleton organization and dynamics. Our studies define the genetic basis of this new neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and neural development, and underscore the critical role of βII-spectrin in the central nervous system.","journal":"medRxiv","year":2020,"id":123989,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":567681,"name":"Keith A. Breau","orcid":"0000-0001-6577-4494","position":1,"is_corresponding":false},{"id":567682,"name":"Blake A. Creighton","orcid":"0000-0001-6574-376X","position":2,"is_corresponding":false},{"id":355070,"name":"Rebecca C. Spillmann","orcid":null,"position":3,"is_corresponding":false},{"id":567683,"name":"Erin Torti","orcid":"0000-0001-5790-1051","position":4,"is_corresponding":false},{"id":567684,"name":"Sruthi Dontu","orcid":"0000-0002-6454-6243","position":5,"is_corresponding":false},{"id":443575,"name":"Swarnendu Tripathi","orcid":"0000-0002-7694-0301","position":6,"is_corresponding":false},{"id":280527,"name":"Deepa Ajit","orcid":"0000-0002-6062-7070","position":7,"is_corresponding":false},{"id":382906,"name":"Kathryn M. Harper","orcid":"0000-0002-6297-0032","position":8,"is_corresponding":false},{"id":496049,"name":"Michael C. Stankewich","orcid":"0000-0003-4472-9162","position":9,"is_corresponding":false},{"id":433290,"name":"Richard Person","orcid":null,"position":10,"is_corresponding":false},{"id":321526,"name":"Yue Si","orcid":"0009-0003-4784-6919","position":11,"is_corresponding":false},{"id":568179,"name":"Elizabeth A. Normand","orcid":null,"position":12,"is_corresponding":false},{"id":568180,"name":"Amy Blevins","orcid":null,"position":13,"is_corresponding":false},{"id":568181,"name":"Alison S. May","orcid":null,"position":14,"is_corresponding":false},{"id":420742,"name":"Louise Bier","orcid":"0000-0001-9692-5611","position":15,"is_corresponding":false},{"id":262908,"name":"Vimla S. Aggarwal","orcid":"0000-0003-4609-0235","position":16,"is_corresponding":false},{"id":567685,"name":"Grazia M.S. Mancini","orcid":"0000-0002-1211-9979","position":17,"is_corresponding":false},{"id":332843,"name":"Marjon A. van Slegtenhorst","orcid":null,"position":18,"is_corresponding":false},{"id":568182,"name":"Kirsten Cremer","orcid":null,"position":19,"is_corresponding":false},{"id":422073,"name":"Jessica Becker","orcid":"0000-0001-7141-2991","position":20,"is_corresponding":false},{"id":567686,"name":"Hartmut Engels","orcid":"0000-0003-1007-1809","position":21,"is_corresponding":false},{"id":461545,"name":"Stefan Aretz","orcid":"0000-0002-5228-1890","position":22,"is_corresponding":false},{"id":567687,"name":"Jennifer MacKenzie","orcid":"0000-0002-3374-8619","position":23,"is_corresponding":false},{"id":286588,"name":"Eva H. Brilstra","orcid":"0000-0001-5793-9623","position":24,"is_corresponding":false},{"id":286602,"name":"Koen L.I. van Gassen","orcid":"0000-0001-7934-0662","position":25,"is_corresponding":false},{"id":456159,"name":"Richard H. van Jaarsveld","orcid":"0000-0001-5247-6965","position":26,"is_corresponding":false},{"id":567688,"name":"Renske Oegema","orcid":"0000-0002-7146-617X","position":27,"is_corresponding":false},{"id":567689,"name":"Gretchen Parsons","orcid":"0000-0001-6495-5541","position":28,"is_corresponding":false},{"id":434524,"name":"Paul R. Mark","orcid":"0000-0002-1020-888X","position":29,"is_corresponding":false},{"id":44516,"name":"Ingo Helbig","orcid":"0000-0001-8486-0558","position":30,"is_corresponding":false},{"id":458016,"name":"Sarah McKeown","orcid":null,"position":31,"is_corresponding":false},{"id":568183,"name":"Robert F. Stratton","orcid":null,"position":32,"is_corresponding":false},{"id":242569,"name":"Benjamin Cogné","orcid":"0000-0002-5503-6292","position":33,"is_corresponding":false},{"id":242573,"name":"Bertrand Isidor","orcid":"0000-0001-6480-126X","position":34,"is_corresponding":false},{"id":266969,"name":"Pilar Cacheiro","orcid":"0000-0002-6335-8208","position":35,"is_corresponding":false},{"id":11700,"name":"Damian Smedley","orcid":"0000-0002-5836-9850","position":36,"is_corresponding":false},{"id":31687,"name":"Helen V. Firth","orcid":"0000-0002-6410-0882","position":37,"is_corresponding":false},{"id":567690,"name":"Tatjana Bierhals","orcid":"0000-0002-6103-105X","position":38,"is_corresponding":false},{"id":567691,"name":"Katja Kloth","orcid":"0000-0001-9521-1385","position":39,"is_corresponding":false},{"id":567692,"name":"Deike Weiss","orcid":"0000-0002-1640-6318","position":40,"is_corresponding":false},{"id":568184,"name":"Cecilia Fairley","orcid":null,"position":41,"is_corresponding":false},{"id":239233,"name":"Joseph T.C. Shieh","orcid":null,"position":42,"is_corresponding":false},{"id":56044,"name":"Amy Kritzer","orcid":"0000-0002-0385-2474","position":43,"is_corresponding":false},{"id":567693,"name":"Parul Jayakar","orcid":"0000-0003-4290-5118","position":44,"is_corresponding":false},{"id":349071,"name":"Evangeline C. Kurtz‐Nelson","orcid":"0000-0002-9418-7915","position":45,"is_corresponding":false},{"id":253991,"name":"Raphael Bernier","orcid":"0000-0003-1854-2804","position":46,"is_corresponding":false},{"id":24417,"name":"Tianyun Wang","orcid":"0000-0002-5179-087X","position":47,"is_corresponding":false},{"id":2125,"name":"Evan E. Eichler","orcid":"0000-0002-8246-4014","position":48,"is_corresponding":false},{"id":331080,"name":"Ingrid M.B.H. van de Laar","orcid":"0000-0002-2523-1230","position":49,"is_corresponding":false},{"id":354481,"name":"Allyn McConkie‐Rosell","orcid":"0000-0003-3742-7799","position":50,"is_corresponding":false},{"id":406933,"name":"Marie McDonald","orcid":"0000-0003-2794-8486","position":51,"is_corresponding":false},{"id":568185,"name":"Jennifer L. Kemppainen","orcid":null,"position":52,"is_corresponding":false},{"id":469171,"name":"Brendan C. Lanpher","orcid":"0000-0002-8899-3582","position":53,"is_corresponding":false},{"id":407002,"name":"Laura Schultz‐Rogers","orcid":"0000-0002-7222-9985","position":54,"is_corresponding":false},{"id":327489,"name":"Lauren Gunderson","orcid":null,"position":55,"is_corresponding":false},{"id":350770,"name":"Pavel N. Pichurin","orcid":"0000-0002-6336-136X","position":56,"is_corresponding":false},{"id":567694,"name":"Grace Yoon","orcid":"0000-0002-0415-4416","position":57,"is_corresponding":false},{"id":567695,"name":"Michael Zech","orcid":"0000-0001-8112-9153","position":58,"is_corresponding":false},{"id":567696,"name":"Robert Jech","orcid":"0000-0002-9732-8947","position":59,"is_corresponding":false},{"id":282683,"name":"Juliane Winkelmann","orcid":"0000-0002-3074-599X","position":60,"is_corresponding":false},{"id":276384,"name":"Undiagnosed Diseases Network","orcid":null,"position":61,"is_corresponding":false},{"id":401670,"name":"Michael T. Zimmermann","orcid":"0000-0001-7073-0525","position":62,"is_corresponding":false},{"id":411077,"name":"Brenda Temple","orcid":"0000-0002-9233-0191","position":63,"is_corresponding":false},{"id":275071,"name":"Sheryl S. Moy","orcid":"0000-0001-7318-7900","position":64,"is_corresponding":false},{"id":242575,"name":"Eric W. Klee","orcid":"0000-0003-2946-5795","position":65,"is_corresponding":false},{"id":355071,"name":"Queenie K.‐G. Tan","orcid":null,"position":66,"is_corresponding":false},{"id":392285,"name":"Damaris N. Lorenzo","orcid":"0000-0002-6856-2988","position":67,"is_corresponding":false},{"id":456967,"name":"Margot A. Cousin","orcid":"0000-0002-6119-9346","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T23:15:03.403566Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}