{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T13:36:55Z","timestamp":1783777015097,"version":"3.55.0"},"reference-count":33,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T00:00:00Z","timestamp":1565222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["18POST34060008"],"award-info":[{"award-number":["18POST34060008"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1RO1NS109358-01"],"award-info":[{"award-number":["1RO1NS109358-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K99HL143036"],"award-info":[{"award-number":["K99HL143036"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Congenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new <jats:italic>bona fide<\/jats:italic> CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>WES of family members of a sporadic and familial form of severe <jats:italic>L1CAM<\/jats:italic> mutation\u2010negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. <jats:italic>Xenopus<\/jats:italic> oocyte experiments were performed to access mutation impact on protein function and expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel inherited protein\u2010damaging mutation (p.Pro605Leu) in <jats:italic>SLC12A6<\/jats:italic>, encoding the K<jats:sup>+<\/jats:sup>\u2010Cl<jats:sup>\u2212<\/jats:sup> cotransporter KCC3, was identified in both affected members of multiplex kindred CHYD110. p.Pro605 is conserved in KCC3 orthologs and among all human KCC paralogs. The p.Pro605Leu mutation maps to the ion\u2010transporting domain, and significantly reduces KCC3\u2010dependent K<jats:sup>+<\/jats:sup> transport. A novel de novo CNV (deletion) was identified in <jats:italic>SLC12A7<\/jats:italic>, encoding the KCC3 paralog and binding partner KCC4, in another family (CHYD130) with sporadic CH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.892","type":"journal-article","created":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T10:08:52Z","timestamp":1565258932000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["<i>SLC12A<\/i> ion transporter mutations in sporadic and familial human congenital hydrocephalus"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5777-7262","authenticated-orcid":false,"given":"Sheng Chih","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Genetics Yale University School of Medicine New Haven CT USA"},{"name":"Laboratory of Human Genetics and Genomics The Rockefeller University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charuta G.","family":"Furey","sequence":"additional","affiliation":[{"name":"Department of Genetics Yale University School of Medicine New Haven CT USA"},{"name":"Department of Neurosurgery Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Genetics Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"August","family":"Allocco","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Nelson\u2010Williams","sequence":"additional","affiliation":[{"name":"Department of Genetics Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilai","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Genetics Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1526-5135","authenticated-orcid":false,"given":"Jason K.","family":"Karimy","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaojie","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Genetics Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Delpire","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Vanderbilt University School of Medicine Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[{"name":"Department of Genetics Yale University School of Medicine New Haven CT USA"},{"name":"Department of Neurosurgery Yale University School of Medicine New Haven CT USA"},{"name":"Department of Cellular &amp; Molecular Physiology Yale University School of Medicine New Haven CT USA"},{"name":"NIH\u2010Yale Centers for Mendelian Genomics, Yale School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,8,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15739-1"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101294"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/416874a"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910672106"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/9898439"},{"issue":"1","key":"e_1_2_7_7_1","first-page":"46","article-title":"Housing and husbandry of Xenopus laevis affect the quality of oocytes for heterologous expression studies","volume":"50","author":"Delpire E.","year":"2011","journal-title":"Journal of the American Association for Laboratory Animal Science"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0061112"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu733"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000319859"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.08.005"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.06.019"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1002"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3970"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aae0546"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60694-8"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp698"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat7615"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04437.x"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws158"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.646"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1754"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1092-107"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24964"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607811200"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.3171\/PED\/2008\/1\/2\/131"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1086\/510137"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi1110s43"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu839"}],"container-title":["Molecular Genetics &amp; 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