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Using agnostic exome sequencing, we identified a nonsense variant creating a premature stop codon in exon 21 of <jats:italic>SPTAN1<\/jats:italic>, and in a second patient we identified an intronic substitution in <jats:italic>SPTAN1<\/jats:italic> prior to exon 50 creating a new donor acceptor site. Neither of these variants has been described previously. Although some of these patients' features are consistent with the known <jats:italic>SPTAN1<\/jats:italic> encephalopathy phenotype, these two children do not have epilepsy, in contrast to reports about nearly every other patient with heterozygous <jats:italic>SPTAN1<\/jats:italic> variants and in all patients with a variant near the C\u2010terminal coding region. Moreover, both children have abnormal thyroid function, which has not been previously reported in association with <jats:italic>SPTAN1<\/jats:italic> variant. We present a detailed discussion of the clinical manifestations of these two unique <jats:italic>SPTAN1<\/jats:italic> variants and provide evidence that both variants result in reduced mRNA expression despite different locations within the gene and clinical phenotypes. These findings expand the motor, cognitive, and behavioral spectrum of the <jats:italic>SPTAN1<\/jats:italic>\u2010associated phenotype and invite speculation about underlying pathophysiologies.<\/jats:p>","DOI":"10.1002\/ajmg.a.40628","type":"journal-article","created":{"date-parts":[[2018,12,12]],"date-time":"2018-12-12T07:30:17Z","timestamp":1544599817000},"page":"2768-2776","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Novel variants in <i>SPTAN1<\/i> without epilepsy: An expansion of the phenotype"],"prefix":"10.1002","volume":"176","author":[{"given":"Valerie","family":"Gartner","sequence":"first","affiliation":[{"name":"Office of the Clinical Director, NHGRI, and NIH Undiagnosed Diseases Program, Office of the Director, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas C.","family":"Markello","sequence":"additional","affiliation":[{"name":"Office of the Clinical Director, NHGRI, and NIH Undiagnosed Diseases Program, Office of the Director, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen","family":"Macnamara","sequence":"additional","affiliation":[{"name":"Office of the Clinical Director, NHGRI, and NIH Undiagnosed Diseases Program, Office of the Director, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"De Biase","sequence":"additional","affiliation":[{"name":"RainDance Technologies, Inc.  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