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Studies in model organisms demonstrate a critical role for ALDH1A2 in embryonic development, yet few pathogenic variants are linked to congenital anomalies in humans. We present three siblings with multiple congenital anomaly syndrome linked to biallelic sequence variants in <jats:italic>ALDH1A2<\/jats:italic>. The major congenital malformations affecting these children include tetralogy of Fallot, absent thymus, diaphragmatic eventration, and talipes equinovarus. Upper airway anomalies, hypocalcemia, and dysmorphic features are newly reported in this manuscript. In vitro functional validation of variants indicated that substitutions reduced the expression of the enzyme. Our clinical and functional data adds to a recent report of biallelic <jats:italic>ALDH1A2<\/jats:italic> pathogenic variants in two families with a similar constellation of congenital malformations. These findings provide further evidence for an autosomal recessive <jats:italic>ALDH1A2<\/jats:italic>\u2010deficient recognizable malformation syndrome involving the diaphragm, cardiac and musculoskeletal systems.<\/jats:p>","DOI":"10.1002\/ajmg.a.62991","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T06:54:53Z","timestamp":1666248893000},"page":"90-99","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<scp><i>ALDH1A2<\/i>\u2010related<\/scp> disorder: A new genetic syndrome due to alteration of the retinoic acid pathway"],"prefix":"10.1002","volume":"191","author":[{"given":"Eyby","family":"Leon","sequence":"first","affiliation":[{"name":"Rare Disease Institute Children's National Hospital  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claris","family":"Nde","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine 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