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The role of rare and\/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (\u22653 EH episodes), 491 AD without a history of eczema herpeticum (ADEH\u2212) and 237 non\u2010atopic control (NA) subjects. Variants were annotated, and a gene\u2010based approach (SKAT\u2010O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Eight genes were identified in the comparison of recurrent ADEH+to ADEH\u2212and NA subjects: <jats:italic>SIDT2<\/jats:italic>, <jats:italic>CLEC7A<\/jats:italic>, <jats:italic>GSTZ1<\/jats:italic>, <jats:italic>TPSG1<\/jats:italic>, <jats:italic>SP110<\/jats:italic>, <jats:italic>RBBP8NL<\/jats:italic>, <jats:italic>TRIM15<\/jats:italic>, and <jats:italic>FRMD3<\/jats:italic>. Silencing <jats:italic>SIDT2<\/jats:italic> and <jats:italic>RBBP8NL<\/jats:italic> in normal human primary keratinocytes (NHPKs) led to significantly increased HSV\u20101 replication. <jats:italic>SIDT2<\/jats:italic>\u2010silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV\u20101 infection. <jats:italic>RBBP8NL<\/jats:italic>\u2010silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing <jats:italic>SIDT2<\/jats:italic> and <jats:italic>RBBP8NL<\/jats:italic> also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>SIDT2<\/jats:italic> and <jats:italic>RBBP8NL<\/jats:italic> participate in keratinocyte's response to HSV\u20101 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.14762","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T18:55:02Z","timestamp":1612810502000},"page":"2510-2523","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum"],"prefix":"10.1111","volume":"76","author":[{"given":"Lianghua","family":"Bin","sequence":"first","affiliation":[{"name":"Department of Pediatrics National Jewish Health Denver CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Malley","sequence":"additional","affiliation":[{"name":"Division of Allergy and Clinical Immunology Johns Hopkins University Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Pediatrics National Jewish Health Denver CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meher","family":"Preethi Boorgula","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Colorado Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Chavan","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Colorado Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Daya","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Colorado Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malaika","family":"Mathias","sequence":"additional","affiliation":[{"name":"Division of Allergy and Clinical Immunology Johns Hopkins University Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautam","family":"Shankar","sequence":"additional","affiliation":[{"name":"Division of Allergy and Clinical Immunology Johns Hopkins University Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Rafaels","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Colorado Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candelaria","family":"Vergara","sequence":"additional","affiliation":[{"name":"Johns Hopkins University, School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Potee","sequence":"additional","affiliation":[{"name":"Precision for Medicine Frederick MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Colorado Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon M.","family":"Hanifin","sequence":"additional","affiliation":[{"name":"Oregon Health &amp; 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