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This variable expressivity suggests that other factors aside from the primary sodium channel variant influence the clinical manifestation. However, identifying such factors has proven challenging in humans.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We perform whole exome sequencing (WES) in a large family in which an\n                      <jats:italic>SCN1A<\/jats:italic>\n                      variant (p.K1372E) is segregating that is associated with a broad spectrum of phenotypes ranging from lack of epilepsy, to febrile seizures and absence seizures, to Dravet syndrome. We assessed the hypothesis that the severity of the SCN1A\u2010related phenotype was affected by alternate alleles at a modifier locus (or loci).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      One of our top candidates identified by WES was a second variant in the\n                      <jats:italic>SCN1A<\/jats:italic>\n                      gene (p.L375S) that was shared exclusively by unaffected carriers of the\n                      <jats:italic>K1372E<\/jats:italic>\n                      allele. To test the hypothesized that L375S variant nullifies the loss\u2010of\u2010function effect of\n                      <jats:italic>K1372E<\/jats:italic>\n                      , we transiently expressed Nav1.1 carrying the two variants in HEK293T cells and compared their biophysical properties with the wild\u2010type (WT) variant, and then co\u2010expressed WT with\n                      <jats:italic>K1372E<\/jats:italic>\n                      or L375S with\n                      <jats:italic>K1372E<\/jats:italic>\n                      in equal quantity and tested the functional consequence. The data demonstrated that co\u2010expression of the\n                      <jats:italic>L375S<\/jats:italic>\n                      and\n                      <jats:italic>K1372E<\/jats:italic>\n                      alleles reversed the loss\u2010of\u2010function property brought by the\n                      <jats:italic>K1372E<\/jats:italic>\n                      variant, whereas WT\u2010K1372E co\u2010expression remained partial loss\u2010of\u2010function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>These results support the hypothesis that L375S counteracts the loss\u2010of\u2010function effect of K1372E such that individuals carrying both alleles in trans do not present epilepsy\u2010related symptoms. We demonstrate that monogenic epilepsies with wide expressivity can be modified by additional variants in the disease gene, providing a novel framework for the gene\u2010phenotype relationship in genetic epilepsies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.17296","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T03:32:25Z","timestamp":1653017545000},"page":"1970-1980","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Whole exome sequencing and co\u2010expression analysis identify an\n                    <i>SCN1A<\/i>\n                    variant that modifies pathogenicity in a family with genetic epilepsy and febrile seizures plus"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0172-429X","authenticated-orcid":false,"given":"Michael F.","family":"Hammer","sequence":"first","affiliation":[{"name":"BIO5 Institute University of Arizona  Tucson Arizona USA"},{"name":"University of Arizona Genomics Core (UAGC) University of Arizona  Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanling","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Biology Indiana University\u2010Purdue University Indianapolis  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Medhane","family":"Cumbay","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences Marian University \u2013 College of Osteopathic Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Pendziwiat","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics University Medical Center Schleswig\u2010Holstein Christian Albrechts University  Kiel Germany"},{"name":"Institute of Clinical Molecular Biology Christian\u2010Albrechts\u2010University of Kiel  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaid","family":"Afawi","sequence":"additional","affiliation":[{"name":"Center for Neuroscience Ben\u2010Gurion University of the Negev  Be'er Sheva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hadassah","family":"Goldberg\u2010Stern","sequence":"additional","affiliation":[{"name":"Epilepsy Unit and EEG Lab Schneider Medical Center  Petah Tikv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurel","family":"Johnstone","sequence":"additional","affiliation":[{"name":"University of Arizona Genomics Core (UAGC) University of Arizona  Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8486-0558","authenticated-orcid":false,"given":"Ingo","family":"Helbig","sequence":"additional","affiliation":[{"name":"Institute of Clinical Molecular Biology Christian\u2010Albrechts\u2010University of Kiel  Kiel 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