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De novo heterozygous missense variants in the <jats:italic>ACTB<\/jats:italic> are implicated in causing Baraitser\u2013Winter cerebrofrontofacial syndrome (BWCFFS; MIM#243310). <jats:italic>ACTB<\/jats:italic> pathogenic variants are rarely associated with intestinal malformations. We report on a rare case of monozygotic twins presenting with proximal small bowel atresia and hydrops in one, and apple\u2010peel bowel atresia and laryngeal dysgenesis in the other. The twin with hydrops could not be resuscitated. Intensive and surgical care was provided to the surviving twin. Rapid trio genome sequencing identified a de novo missense variant in <jats:italic>ACTB<\/jats:italic> (NM_00101.3:c.1043C&gt;T; p.(Ser348Leu)) that guided the care plan. The identical variant subsequently was identified in the demised twin. To characterize the functional effect, the variant was recreated as a pseudoheterozygote in a haploid wild\u2010type <jats:italic>S. cerevisiae<\/jats:italic> strain. There was an obvious growth defect of the y<jats:italic>ACT1<\/jats:italic><jats:sup>S348L\/WT<\/jats:sup> pseudoheterozygote compared to a y<jats:italic>ACT1<\/jats:italic><jats:sup>WT\/WT<\/jats:sup> strain when grown at 22\u00b0C but not when grown at 30\u00b0C, consistent with the y<jats:italic>ACT1<\/jats:italic> S348L variant having a functional defect that is dominant over the wild\u2010type allele. The functional results provide supporting evidence that the Ser348Leu variant is likely to be a pathogenic variant, including being associated with intestinal malformations in BWCFFS, and can demonstrate variable expressivity within monozygotic twins.<\/jats:p>","DOI":"10.1002\/ajmg.a.62631","type":"journal-article","created":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T09:05:42Z","timestamp":1640941542000},"page":"1299-1306","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A de novo <scp><i>ACTB<\/i><\/scp> gene pathogenic variant in identical twins with phenotypic variation for hydrops and jejunal atresia"],"prefix":"10.1002","volume":"188","author":[{"given":"Kristina","family":"Sibbin","sequence":"first","affiliation":[{"name":"Starship Child Health Auckland City Hospital  Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Yap","sequence":"additional","affiliation":[{"name":"Starship Child Health Auckland City Hospital  Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis","family":"Nyaga","sequence":"additional","affiliation":[{"name":"Liggins Institute The University of Auckland  Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raoul","family":"Heller","sequence":"additional","affiliation":[{"name":"Starship Child Health Auckland City Hospital  Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Evans","sequence":"additional","affiliation":[{"name":"Starship Child Health Auckland City Hospital  Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"Strachan","sequence":"additional","affiliation":[{"name":"Starship Child Health Auckland City Hospital  Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salam","family":"Alburaiky","sequence":"additional","affiliation":[{"name":"Starship Child Health Auckland City Hospital  Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han M. 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