{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T12:45:22Z","timestamp":1700570722885},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2012,7,27]],"date-time":"2012-07-27T00:00:00Z","timestamp":1343347200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Holoprosencephaly is the most frequent congenital malformation of the forebrain in humans. It is anatomically classified by the relative degree of abnormal formation and separation of the developing central nervous system. Mutations of <jats:italic>ZIC2<\/jats:italic> are the second most common heterozygous variations detected in holoprosencephaly (HPE) patients. Mutations in most known HPE genes typically result in variable phenotypes that rage from classic alobar HPE to microforms represented by hypotelorism, solitary central maxillary incisor (SCMI), and cleft lip\/palate, among others. Patients with HPE owing to <jats:italic>ZIC2<\/jats:italic> mutations have recently been described by a distinct phenotype compared with mutations in other HPE causative genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We report the comparison of <jats:italic>ZIC2<\/jats:italic> molecular findings by Sanger bidirectional DNA sequencing and ad hoc genotyping in a cohort of 105 Brazilian patients within the clinical spectrum of HPE, including classic and microform groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We detected a total of five variants in the <jats:italic>ZIC2<\/jats:italic> gene: a common histidine tract expansion c.716_718dup (p.His239dup), a rare c.1377_1391del_homozygous (p.Ala466_470del, or Ala 15 to 10 contraction), a novel intronic c.1239+18G&gt;A variant, a novel frameshift c.1215dupC (p.Ser406Glnfs*11), and a c.1401_1406dup (p.Ala469_470dup, or alanine tract expansion to 17 residues).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>From these patients, only the latter two mutations found in classic HPE are likely to be medically significant. In contrast, variants detected in the microform group are not likely to be pathogenic. We show conclusively that the histidine tract expansion is a polymorphic alteration that demonstrates considerable differences in allele frequencies across different ethnic groups. Therefore, careful population studies of rare variants can improve genotype\u2010phenotype correlations. Birth Defects Research (Part A) 2012. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.23047","type":"journal-article","created":{"date-parts":[[2012,7,28]],"date-time":"2012-07-28T05:35:36Z","timestamp":1343453736000},"page":"912-917","source":"Crossref","is-referenced-by-count":5,"title":["Comparison of mutation findings in <i>ZIC2<\/i> between microform and classical holoprosencephaly in a Brazilian cohort"],"prefix":"10.1002","volume":"94","author":[{"given":"Lucilene A.","family":"Ribeiro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erich","family":"Roessler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E.","family":"Pineda\u2010Alvarez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MaryPat","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Settara","family":"Chandrasekharappa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Richieri\u2010Costa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian","family":"Muenke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,7,27]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2004.01.004"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2006.02.011"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.07.001"},{"key":"e_1_2_6_5_1","first-page":"431","article-title":"Middle interhemispheric fusion: an unusual variant of holoprosencephaly","volume":"14","author":"Barkovich AJ","year":"1993","journal-title":"Am J Neuroradiol"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80560-7"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.037176"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-005-0097-6"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21016"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320450115"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/2484"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.8.791"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.10221"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi037"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0714-06.2006"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20295"},{"key":"e_1_2_6_17_1","first-page":"443","article-title":"No association of the polyhistidine tract polymorphism of the ZIC2 gene with neural tube defects in a South American (ECLAM) population","volume":"1","author":"Costa\u2010Lima MA","year":"2008","journal-title":"Mol Med Report"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-2-8"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2005.00418.x"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/76074"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2463"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0b013e32833f56d5"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20402"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399407000440"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420160304"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100339"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/nen.0b013e3180986e1b"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.4.1618"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.70"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30253"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-011-1078-6"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31378"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30247"},{"key":"e_1_2_6_34_1","first-page":"294","article-title":"Holoprosencephaly: birth data, genetic and demographic analyses of 30 families","volume":"11","author":"Roach E","year":"1975","journal-title":"Birth Defects Orig Artic Ser"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1196-357"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2235734100"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi222"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20982"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30236"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2012.01.005"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.073049"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30240"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/9718"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn197"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(04)00027-9"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32844"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.10032"}],"container-title":["Birth Defects Research Part A: Clinical and Molecular Teratology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdra.23047","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdra.23047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T12:11:45Z","timestamp":1700568705000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdra.23047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,7,27]]},"references-count":46,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2012,11]]}},"alternative-id":["10.1002\/bdra.23047"],"URL":"https:\/\/doi.org\/10.1002\/bdra.23047","archive":["Portico"],"relation":{},"ISSN":["1542-0752","1542-0760"],"issn-type":[{"value":"1542-0752","type":"print"},{"value":"1542-0760","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,7,27]]}}}