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PHS may also include a wide range of clinical phenotypes affecting multiple organ systems including congenital anomalies of the kidney and urinary tract (CAKUT). The observed clinical phenotypes are consistent with the essential role of <jats:italic>GLI3,<\/jats:italic> a transcriptional effector in the hedgehog (Hh) signaling pathway, in organogenesis. However, the mechanisms by which truncation of <jats:italic>GLI3<\/jats:italic> in PHS results in such a variety of clinical phenotypes with variable severity, even within the same organ, remain unclear. In this study we focus on presentation of CAKUT in PHS. A systematic analysis of reported PHS patients (<jats:italic>n<\/jats:italic>\u00a0=\u00a078) revealed a prevalence of 26.9% (21\/78) of CAKUT. Hypoplasia (\u00b1 dysplasia) and agenesis were the two main types of CAKUT; bilateral and unilateral CAKUT were reported with equal frequency. Examination of clinical phenotypes with CAKUT revealed a significant association between CAKUT and craniofacial defects, bifid epiglottis and a Disorder of Sex Development, specifically affecting external genitalia. Lastly, we determined that PHS patients with CAKUT predominately had substitution type variants (as opposed to deletion type variants in non\u2010CAKUT PHS patients) in the middle third of the <jats:italic>GLI3<\/jats:italic> gene. These results provide a foundation for future work aimed at uncovering the molecular mechanisms by which variant <jats:italic>GLI3<\/jats:italic> result in the wide range and severity of clinical features observed in PHS.<\/jats:p>","DOI":"10.1002\/ajmg.c.31999","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T12:04:01Z","timestamp":1664280241000},"page":"264-278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pallister\u2010Hall syndrome, <scp>GLI3<\/scp>, and kidney malformation"],"prefix":"10.1002","volume":"190","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2845-5448","authenticated-orcid":false,"given":"Kathryn","family":"McClelland","sequence":"first","affiliation":[{"name":"Program in Developmental and Stem Cell Biology The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weili","family":"Li","sequence":"additional","affiliation":[{"name":"The Centre for Applied Genomics, Genetics and Genome Biology The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1767-6464","authenticated-orcid":false,"given":"Norman D.","family":"Rosenblum","sequence":"additional","affiliation":[{"name":"Program in Developmental and Stem Cell Biology The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Division of Nephrology, Department of Paediatrics University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12952"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.111.4.e382"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2020-106948"},{"key":"e_1_2_8_5_1","volume-title":"Pallister\u2010Hall syndrome \u2010 PubMed GeneReviews","author":"Biesecker L. 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