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Variants in <jats:italic>SPTBN4<\/jats:italic> disrupt the cytoskeletal machinery that controls proper localization of ion channels and the function of axonal domains, thereby generating severe neurological dysfunction. We set out to analyze the genetic causes and describe the clinical spectrum of suspected cases of NEDHND. Variant screening was done by whole exome sequencing; clinical phenotypes were described according to the human phenotype ontology, and histochemical analysis was performed with disease-specific antibodies. We report four families with five patients harboring novel homozygous and compound heterozygous <jats:italic>SPTBN4<\/jats:italic> variants, amongst them a multi-exon deletion of <jats:italic>SPTBN4<\/jats:italic>. All patients presented with the key features of NEDHND; severe muscular hypotonia, dysphagia, absent speech, gross motor, and mental retardation. Additional symptoms comprised horizontal nystagmus, epileptiform discharges in EEG without manifest seizures, and choreoathetosis. Muscle histology revealed both characteristics of myopathy and of neuropathy. This report expands the <jats:italic>SPTBN4<\/jats:italic> variant spectrum, highlights the spectrum of morphological phenotypes of NEDHND-patients, and reveals clinical similarities between the NEDHND, non-5q SMA, and congenital myopathies.<\/jats:p>","DOI":"10.1038\/s41431-021-00846-5","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T07:02:51Z","timestamp":1616742171000},"page":"1121-1128","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Novel bi-allelic variants expand the SPTBN4-related genetic and phenotypic spectrum"],"prefix":"10.1038","volume":"29","author":[{"given":"Markus","family":"Buelow","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"S\u00fc\u00dfmuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie D.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omid","family":"Aryani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1981-7550","authenticated-orcid":false,"given":"Claudia","family":"Castiglioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Stenzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2824-3891","authenticated-orcid":false,"given":"Markus","family":"Schuelke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4769-7322","authenticated-orcid":false,"given":"Ellen","family":"Knierim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"846_CR1","doi-asserted-by":"publisher","first-page":"C121","DOI":"10.1152\/ajpcell.1983.244.3.C121","volume":"244","author":"S Goodman","year":"1983","unstructured":"Goodman S, Shiffer K. 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