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A certain genotype\u2013phenotype correlation has been proposed according to the type and location of the mutation. Herein, we report three novel cases with de novo <jats:italic>SPTAN1<\/jats:italic> mutations, one of them associated to a mild phenotype not previously described. They range from (1) severe developmental encephalopathy with ataxia and a mild cerebellar atrophy, without epilepsy; (2) moderate intellectual disability, severe language delay, ataxia and tremor; (3) normal intelligence, chronic migraine, and generalized tonic\u2013clonic seizures. Remarkably, all these patients showed brain MRI abnormalities, being of special interest the subependymal heterotopias detected in the latter patient. Thus we extend the <jats:italic>SPTAN1<\/jats:italic>\u2010related phenotypic spectrum, both in its radiological and clinical involvement. Furthermore, after systematic analysis of all the patients so far reported, we noted an excess of male versus female patients (20:9, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.04), more pronounced among the milder phenotypes. Consequently, some protection factor might be suspected among female carriers, which if confirmed should be considered when establishing the pathogenicity of milder genetic variants in this gene.<\/jats:p>","DOI":"10.1002\/ajmg.a.62507","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T09:55:49Z","timestamp":1632995749000},"page":"147-159","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Extending the clinical phenotype of <scp><i>SPTAN1<\/i><\/scp>: From <scp>DEE5<\/scp> to migraine, epilepsy, and subependymal heterotopias without intellectual disability"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6027-376X","authenticated-orcid":false,"given":"Ana Victoria","family":"Marco Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Genetics Unit Hospital Universitari i Polit\u00e8cnic La Fe  Valencia Spain"},{"name":"Neuropediatrics 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