{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T16:23:48Z","timestamp":1764174228639,"version":"3.41.0"},"reference-count":18,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,12,24]],"date-time":"2015-12-24T00:00:00Z","timestamp":1450915200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK081702"],"award-info":[{"award-number":["DK081702"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:sec><jats:label\/><jats:p>We studied two brothers who presented in the newborn period with cardiac, renal, and hepatic anomalies that were initially suggestive of ALGS, although no mutations in<jats:italic>JAG1<\/jats:italic>or<jats:italic>NOTCH2<\/jats:italic>were identified. Exome sequencing demonstrated compound heterozygous mutations in the<jats:italic>NEK8<\/jats:italic>gene (Never in mitosis A\u2010related Kinase 8), a ciliary kinase indispensable for cardiac and renal development based on murine studies. The mutations included a c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C&gt;T variant (p.Thr348Met) in the highly conserved RCC1 (Regulation of Chromosome Condensation 1) domain. The RCC1 domain is crucial for localization of the<jats:italic>NEK8<\/jats:italic>protein to the centrosomes and cilia. Mutations in<jats:italic>NEK8<\/jats:italic>have been previously reported in three fetuses (from a single family) with renal\u2010hepatic\u2010pancreatic dysplasia 2 (RHPD2), similar to Ivemark syndrome, and in three individuals with nephronophthisis (NPHP9). This is the third report of disease\u2010causing mutations in the<jats:italic>NEK8<\/jats:italic>gene in humans and only the second describing multi\u2010organ involvement. The clinical features we describe differ from those in the previously published report in that (1) a pancreatic phenotype was not observed in the individuals reported here, (2) there were more prominent cardiac findings, (consistent with observations in murine models), and (3) we observed bile duct hypoplasia rather than ductal plate malformation. The patients reported here expand our understanding of the NEK8\u2010associated phenotype. Our findings highlight the variable phenotypic expressivity and the spectrum of clinical manifestations due to mutations in the<jats:italic>NEK8<\/jats:italic>gene. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.37512","type":"journal-article","created":{"date-parts":[[2015,12,24]],"date-time":"2015-12-24T11:44:39Z","timestamp":1450957479000},"page":"750-753","source":"Crossref","is-referenced-by-count":22,"title":["Compound heterozygous mutations in<i>NEK8<\/i>in siblings with end\u2010stage renal disease with hepatic and cardiac anomalies"],"prefix":"10.1002","volume":"170","author":[{"given":"Ramakrishnan","family":"Rajagopalan","sequence":"first","affiliation":[{"name":"Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania Philadelphia 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Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karlene","family":"Coleman","sequence":"additional","affiliation":[{"name":"Marcus Autism Center Children's Healthcare of Atlanta Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rene","family":"Romero","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics Emory University School of Medicine Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen M.","family":"Loomes","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Piccoli","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcella","family":"Devoto","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Department of Biostatistics and Epidemiology, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Department of Molecular Medicine University La Sapienza Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy B.","family":"Spinner","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,12,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1651-2227.1959.tb16011.x","article-title":"Familial dysplasia of kidneys, liver and pancreas: A probably genetically determined syndrome","volume":"48","author":"Ivemark BI","year":"1959","journal-title":"Acta 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