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Genet."],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in\n                    <jats:italic>CYP26B1<\/jats:italic>\n                    have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with\n                    <jats:italic>CYP26B1<\/jats:italic>\n                    -related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability\u2014and compound heterozygous\n                    <jats:italic>CYP26B1<\/jats:italic>\n                    variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in\n                    <jats:italic>CYP26B1<\/jats:italic>\n                    : c.1083C\u2009&gt;\u2009A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~\u20093.5\u2009\u00d7\u2009decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7\u00d7\u2009and 2.3\u00d7\u2009reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in\n                    <jats:italic>CYP26B1<\/jats:italic>\n                    result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.\n                  <\/jats:p>","DOI":"10.1007\/s00439-023-02598-2","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T04:02:34Z","timestamp":1695787354000},"page":"1571-1586","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["CYP26B1-related disorder: expanding the ends of the spectrum through clinical and molecular evidence"],"prefix":"10.1007","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9114-9481","authenticated-orcid":false,"given":"Karina C.","family":"Silveira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9482-8647","authenticated-orcid":false,"given":"Inara Chacon","family":"Fonseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7221-1187","authenticated-orcid":false,"given":"Connor","family":"Oborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6967-5426","authenticated-orcid":false,"given":"Parker","family":"Wengryn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saima","family":"Ghafoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9050-6061","authenticated-orcid":false,"given":"Alexander","family":"Beke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ema S.","family":"Dreseris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Iacovone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie-Lynn","family":"Soltys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riyana","family":"Babul-Hirji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osvaldo","family":"Artigalas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Antolini-Tavares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6090-4437","authenticated-orcid":false,"given":"Anne-Claude","family":"Gingras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-4730","authenticated-orcid":false,"given":"Denise P.","family":"Cavalcanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9479-4232","authenticated-orcid":false,"given":"Peter","family":"Kannu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,27]]},"reference":[{"key":"2598_CR1","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1002\/humu.23626","volume":"39","author":"AN Abou Tayoun","year":"2018","unstructured":"Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, Harrison SM (2018) Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion. 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