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Other <jats:italic>ENPP1<\/jats:italic>\u2010related phenotypes include pseudoxanthoma elasticum, hypophosphatemic rickets, and Cole disease. We studied four children from two Bedouin consanguineous families who presented with severe clinical phenotype including thrombocytopenia, hypoglycemia, hepatic, and neurologic manifestations. Initial working diagnosis included congenital infection; however, patients remained without a definitive diagnosis despite extensive workup. Consequently, we investigated a potential genetic etiology. Whole exome sequencing (WES) was performed for affected children and their parents. Following the identification of a novel mutation in the <jats:italic>ENPP1<\/jats:italic> gene, we characterized this novel multisystemic presentation and revised relevant imaging studies. Using WES, we identified a novel homozygous mutation (c.556G\u2009&gt;\u2009C; p.Gly186Arg) in <jats:italic>ENPP1<\/jats:italic> which affects a highly conserved protein domain (somatomedin B2). <jats:italic>ENPP1<\/jats:italic>\u2010associated genetic diseases exhibit phenotypic heterogeneity depending on mutation type and location. Follow\u2010up clinical characterization of these families allowed us to revise and detect new features of systemic calcifications, which established the diagnosis of GACI, expanding the phenotypic spectrum associated with <jats:italic>ENPP1<\/jats:italic> mutations. Our findings demonstrate that this novel <jats:italic>ENPP1<\/jats:italic> founder mutation can cause a fatal multisystemic phenotype, mimicking severe congenital infection. This also represents the first reported mutation affecting the SMB2 domain, associated with GACI.<\/jats:p>","DOI":"10.1002\/ajmg.a.61334","type":"journal-article","created":{"date-parts":[[2019,8,24]],"date-time":"2019-08-24T09:59:00Z","timestamp":1566640740000},"page":"2112-2118","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Novel homozygous <i>ENPP1<\/i> mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6975-4909","authenticated-orcid":false,"given":"Orna","family":"Staretz\u2010Chacham","sequence":"first","affiliation":[{"name":"Metabolic Clinic, Pediatric Division, Soroka Medical Center Ben\u2010Gurion University  Be'er Sheva Israel"},{"name":"Department of Neonatology, Soroka University Medical Center, Faculty of Health Sciences School 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Ramat\u2010Gan Israel"},{"name":"Talpiot Medical Leadership Program, Department of Pediatrics B and Pediatric Nephrology Unit Sheba Medical Center  Ramat\u2010Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oren","family":"Pleniceanu","sequence":"additional","affiliation":[{"name":"Edmond and Lily Safra Children's Hospital Sheba Medical Center  Ramat\u2010Gan Israel"},{"name":"Sackler School of Medicine Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Anikster","sequence":"additional","affiliation":[{"name":"Sackler School of Medicine Tel Aviv University  Tel Aviv Israel"},{"name":"Metabolic Disease Unit Edmond and Lily Safra Children's Hospital, Sheba Medical Center  Ramat\u2010Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nechama","family":"Shalva","sequence":"additional","affiliation":[{"name":"Metabolic Disease Unit Edmond and Lily Safra Children's 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Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrikant M.","family":"Mane","sequence":"additional","affiliation":[{"name":"Department of Genetics Yale University School of Medicine  New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7130-0030","authenticated-orcid":false,"given":"Friedhelm","family":"Hildebrandt","sequence":"additional","affiliation":[{"name":"Department of Medicine Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asaf","family":"Vivante","sequence":"additional","affiliation":[{"name":"Edmond and Lily Safra Children's Hospital Sheba Medical Center  Ramat\u2010Gan Israel"},{"name":"Sackler School of Medicine Tel Aviv University  Tel Aviv Israel"},{"name":"Talpiot Medical Leadership Program, Department of Pediatrics B and Pediatric Nephrology Unit Sheba Medical Center  Ramat\u2010Gan 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