{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T19:52:33Z","timestamp":1786823553656,"version":"build-2736575974"},"reference-count":23,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,1,8]],"date-time":"2022-01-08T00:00:00Z","timestamp":1641600000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>WAC<\/jats:italic>\u2010related intellectual disability, also known as DeSanto\u2013Shinawi syndrome, is a rare autosomal dominant genetic disorder caused by pathogenic variants in <jats:italic>WAC<\/jats:italic> gene. This syndrome is characterized by developmental delay, intellectual disability, behavioral abnormalities, and dysmorphic facial features, including deep\u2010set eyes, flat nasal bridge, bulbous nasal tip, and synophrys. Chromosomal deletions at 10p12p11 encompassing <jats:italic>WAC<\/jats:italic> gene have been described in patients with a similar phenotype, presenting with developmental delay, intellectual disability, visual impairments, abnormal behavior, and dysmorphic features. An important clinical difference between the two groups of patients, is that those with large deletions frequently present with congenital cardiac defects, which were rarely reported in patients with pathogenic variants in <jats:italic>WAC<\/jats:italic>. The genes underlying heart defects in patients with the deletion have not yet been fully clarified. Here, we describe two unrelated Portuguese patients with <jats:italic>de novo<\/jats:italic> pathogenic variants in <jats:italic>WAC<\/jats:italic> gene, previously unreported in the literature. Both patients present with microcephaly, developmental delay, intellectual disability, behavioral problems, and facial dysmorphisms. Interestingly, the youngest patient has a severe congenital cardiac malformation, showing that intragenic pathogenic <jats:italic>WAC<\/jats:italic> variants can also be associated with heart defects. Therefore, this report expands the phenotypic and genotypic spectrum of this rare syndrome and provides deeper insights by comparing the clinical features of our patients with previously reported cases.<\/jats:p>","DOI":"10.1002\/ajmg.a.62636","type":"journal-article","created":{"date-parts":[[2022,1,8]],"date-time":"2022-01-08T12:33:34Z","timestamp":1641645214000},"page":"1311-1316","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Congenital heart defects associated with pathogenic variants in <scp><i>WAC<\/i><\/scp> gene: Expanding the phenotypic and genotypic spectrum of <scp>DeSanto\u2013Shinawi<\/scp> syndrome"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3856-244X","authenticated-orcid":false,"given":"Rita","family":"Quental","sequence":"first","affiliation":[{"name":"Department of Medical Genetics Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o (CHUSJ)  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Neurodevelopment Unit, Department of Pediatrics CHUSJ  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmeralda","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Unit, Department of Pediatrics CHUSJ  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edite","family":"Serrano Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology CHUSJ  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Oliveira","sequence":"additional","affiliation":[{"name":"CGPP \u2010 Centro de Gen\u00e9tica Preditiva e Preventiva IBMC \u2010 Instituto de Biologia Molecular e Celular, Universidade do Porto  Porto Portugal"},{"name":"i3S \u2010 Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o","family":"Parente Freixo","sequence":"additional","affiliation":[{"name":"CGPP \u2010 Centro de Gen\u00e9tica Preditiva e Preventiva IBMC \u2010 Instituto de Biologia Molecular e Celular, Universidade do Porto  Porto Portugal"},{"name":"i3S \u2010 Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Le\u00e3o","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o (CHUSJ)  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,1,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37686"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2020.12.010"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/8820966"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20320"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1206524"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2015-103069"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004772"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa206"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac9396"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13908"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes11030344"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.282"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2011.154"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32088"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2015.4"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.4103\/apc.APC_20_20"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.10078"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38703"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000488815"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.71"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.01.024"},{"issue":"10","key":"e_1_2_9_24_1","first-page":"802","article-title":"WAC gene pathogenic variation cause DeSanto\u2010Shinawi syndrome with electrical status epilepticus during sleep","volume":"57","author":"Zhang Y. 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