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Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of <jats:italic>ALX4<\/jats:italic>. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss\u2010of\u2010function variants of <jats:italic>TWIST1<\/jats:italic>, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in <jats:italic>ALX4<\/jats:italic> and <jats:italic>TWIST1<\/jats:italic>. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable <jats:italic>ALX4<\/jats:italic>\u2010related EPF phenotype. This report demonstrates comorbid disorders of Saethre\u2010Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic <jats:italic>ALX4<\/jats:italic> variants. To our knowledge this is the first instance of <jats:italic>ALX4<\/jats:italic> and <jats:italic>TWIST1<\/jats:italic> variants acting synergistically to cause a unique phenotype influencing skull ossification.<\/jats:p>","DOI":"10.1002\/ajmg.a.62036","type":"journal-article","created":{"date-parts":[[2020,12,27]],"date-time":"2020-12-27T09:26:23Z","timestamp":1609061183000},"page":"916-922","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Vertical transmission of a large calvarial ossification defect due to heterozygous variants of <scp><i>ALX4<\/i><\/scp> and <scp><i>TWIST1<\/i><\/scp>"],"prefix":"10.1002","volume":"185","author":[{"given":"Michelle E.","family":"Walters","sequence":"first","affiliation":[{"name":"Division of Dermatology Harbor\u2010UCLA Medical Center  Torrance California 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