{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:00:37Z","timestamp":1791327637439,"version":"4.3.1"},"reference-count":75,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,2,16]],"date-time":"2016-02-16T00:00:00Z","timestamp":1455580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201012\u2010BSV1\u20100007\u201001"],"award-info":[{"award-number":["ANR\u201012\u2010BSV1\u20100007\u201001"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006005","name":"Agence de la Biom\u00e9decine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>Holoprosencephaly (<jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content>) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content> and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content> may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high\u2010throughput sequencing approaches to identify mutations in <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content> subjects. Here, we report two <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content> families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi\u2010lobar <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content>, we found mutations in two genes involved in <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content>, <jats:italic><jats:styled-content style=\"fixed-case\">SHH<\/jats:styled-content><\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">DISP1<\/jats:styled-content><\/jats:italic>, inherited respectively from the father and the mother. The second reported case is a family with a 9\u2010year\u2010old girl presenting lobar <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content>, harbouring two compound heterozygous mutations in <jats:italic><jats:styled-content style=\"fixed-case\">DISP1<\/jats:styled-content><\/jats:italic>. Together, these cases of digenic inheritance and autosomal recessive <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content> suggest that in some families, several genetic events are necessary to cause <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content>. This study highlights the complexity of <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content> inheritance and has to be taken into account by clinicians to improve <jats:styled-content style=\"fixed-case\">HPE<\/jats:styled-content> genetic counselling.<\/jats:p>","DOI":"10.1111\/cge.12722","type":"journal-article","created":{"date-parts":[[2016,1,10]],"date-time":"2016-01-10T09:40:54Z","timestamp":1452418854000},"page":"659-668","source":"Crossref","is-referenced-by-count":48,"title":["Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing"],"prefix":"10.1111","volume":"89","author":[{"given":"C.","family":"Mouden","sequence":"first","affiliation":[{"name":"UMR6290 Institut de G\u00e9n\u00e9tique et D\u00e9veloppement de Rennes Universit\u00e9 de Rennes 1  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Dubourg","sequence":"additional","affiliation":[{"name":"UMR6290 Institut de G\u00e9n\u00e9tique et D\u00e9veloppement de Rennes Universit\u00e9 de Rennes 1  Rennes France"},{"name":"Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire et G\u00e9nomique C.H.U. de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Carr\u00e9","sequence":"additional","affiliation":[{"name":"Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire et G\u00e9nomique C.H.U. de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Rose","sequence":"additional","affiliation":[{"name":"UMR1085 Institut de Recherche sur la Sant\u00e9, l'Environnement et le Travail Universit\u00e9 de Rennes 1  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Quelin","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique Clinique C.H.U. de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Akloul","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique Clinique C.H.U. de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Hamdi\u2010Roz\u00e9","sequence":"additional","affiliation":[{"name":"UMR6290 Institut de G\u00e9n\u00e9tique et D\u00e9veloppement de Rennes Universit\u00e9 de Rennes 1  Rennes France"},{"name":"Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire et G\u00e9nomique C.H.U. de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Viot","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique M\u00e9dicale Maternit\u00e9 Port Royal  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Salhi","sequence":"additional","affiliation":[{"name":"Foetopathologie et Anatomie Pathologique P\u00e9diatrique H\u00f4pital Cochin  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Darnault","sequence":"additional","affiliation":[{"name":"Service de Radiologie et Imagerie M\u00e9dicale C.H.U. de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Odent","sequence":"additional","affiliation":[{"name":"UMR6290 Institut de G\u00e9n\u00e9tique et D\u00e9veloppement de Rennes Universit\u00e9 de Rennes 1  Rennes France"},{"name":"Service de G\u00e9n\u00e9tique Clinique C.H.U. de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Dup\u00e9","sequence":"additional","affiliation":[{"name":"UMR6290 Institut de G\u00e9n\u00e9tique et D\u00e9veloppement de Rennes Universit\u00e9 de Rennes 1  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"David","sequence":"additional","affiliation":[{"name":"UMR6290 Institut de G\u00e9n\u00e9tique et D\u00e9veloppement de Rennes Universit\u00e9 de Rennes 1  Rennes France"},{"name":"Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire et G\u00e9nomique C.H.U. de Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,2,16]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20479"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100339"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.10587"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-002-0695-5"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2012.01.005"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.010132"},{"key":"e_1_2_6_8_1","volume-title":"GeneReviews(R)","author":"Solomon BD","year":"1993"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-014-1487-4"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0117418"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-002-0709-3"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1159\/000302285"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33466"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.07.001"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.110"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq556"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/1749-8104-8-25"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32909"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101008"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2013-101713"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1068"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1543607"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399407000440"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.13.2479"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.3715005"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp190"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1001025"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.097857.109"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.176601"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.092619.109"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr407"},{"key":"e_1_2_6_32_1","first-page":"7.20","article-title":"Predicting functional effect of human missense mutations using PolyPhen\u20102","author":"Adzhubei I","year":"2013","journal-title":"Curr Protoc Hum Genet"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22225"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu733"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405161200"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(02)02640-9"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.01.022"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-009-0628-7"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33618"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01563"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00178"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)01147-8"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20295"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20056"},{"key":"e_1_2_6_46_1","first-page":"97","article-title":"Functional analysis of mutations in TGIF associated with holoprosencephaly","volume":"90","author":"El\u2010Jaick KB","year":"2007","journal-title":"Mol Cell Biol"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-0454"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.4161\/15384101.2014.946830"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30236"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1987.tb02800.x"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.2164\/jandrol.108.005314"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ando.2010.02.005"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102822"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.4.379"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1086\/341031"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1196-357"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.11.1847"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.86.4.293"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/2484"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004390100537"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.073049"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34029"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/9718"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200540"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31377"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2008.063818"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-010-0797-4"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/76074"},{"key":"e_1_2_6_69_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00439-002-0862-8","article-title":"Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations","volume":"112","author":"Aguilella C","year":"2003","journal-title":"Hum Genet"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31370"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31369"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2235734100"},{"key":"e_1_2_6_73_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01606.x"},{"key":"e_1_2_6_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.05.012"},{"key":"e_1_2_6_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2009.05.005"},{"key":"e_1_2_6_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2014.05.023"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcge.12722","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.12722","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T13:55:07Z","timestamp":1696254907000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.12722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,16]]},"references-count":75,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016,6]]}},"alternative-id":["10.1111\/cge.12722"],"URL":"https:\/\/doi.org\/10.1111\/cge.12722","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,2,16]]}}}