{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:00:36Z","timestamp":1791327636013,"version":"4.3.1"},"reference-count":49,"publisher":"BMJ","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2011,9,2]]},"published-print":{"date-parts":[[2011,11]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Holoprosencephaly (HPE) is the most common forebrain defect in humans. It results from incomplete midline cleavage of the prosencephalon.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A large European series of 645 HPE probands (and 699 relatives), consisting of 51% fetuses and 49% liveborn children, is reported.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Mutations in the four main genes involved in HPE (<jats:italic>SHH<\/jats:italic>, <jats:italic>ZIC2<\/jats:italic>, <jats:italic>SIX3<\/jats:italic>, <jats:italic>TGIF<\/jats:italic>) were identified in 25% of cases. The <jats:italic>SHH<\/jats:italic>, <jats:italic>SIX3<\/jats:italic>, and <jats:italic>TGIF<\/jats:italic> mutations were inherited in more than 70% of these cases, whereas 70% of the mutations in <jats:italic>ZIC2<\/jats:italic> occurred <jats:italic>de novo<\/jats:italic>. Moreover, rearrangements were detected in 22% of the 260 patients screened by array comparative genomic hybridisation. 15 probands had two mutations providing additional support for the \u2018multiple-hit process\u2019 in HPE. There was a positive correlation between the severity of the brain malformation and facial features for <jats:italic>SHH<\/jats:italic>, <jats:italic>SIX3<\/jats:italic>, and <jats:italic>TGIF<\/jats:italic>, but no such correlation was found for <jats:italic>ZIC2<\/jats:italic> mutations. The most severe HPE types were associated with <jats:italic>SIX3<\/jats:italic> and <jats:italic>ZIC2<\/jats:italic> mutations, whereas microforms were associated with <jats:italic>SHH<\/jats:italic> mutations. The study focused on the associated brain malformations, including neuronal migration defects, which predominated in individuals with <jats:italic>ZIC2<\/jats:italic> mutations, and neural tube defects, which were frequently associated with <jats:italic>ZIC2<\/jats:italic> (rachischisis) and <jats:italic>TGIF<\/jats:italic> mutations. Extracraniofacial features were observed in 27% of the individuals in this series (up to 40% of those with <jats:italic>ZIC2<\/jats:italic> mutations) and a significant correlation was found between renal\/urinary defects and mutations of <jats:italic>SHH<\/jats:italic> and <jats:italic>ZIC2<\/jats:italic>.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>An algorithm is proposed based on these new phenotype\u2013genotype correlations, to facilitate molecular analysis and genetic counselling for HPE.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2011-100339","type":"journal-article","created":{"date-parts":[[2011,9,23]],"date-time":"2011-09-23T20:32:08Z","timestamp":1316809928000},"page":"752-760","source":"Crossref","is-referenced-by-count":101,"title":["New findings for phenotype\u2013genotype correlations in a large European series of holoprosencephaly 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