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Genet."],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The autosomal dominant multisystemic Alagille Syndrome (ALGS) is an important cause of pediatric cholestasis. ALGS is associated with pathogenic variants in JAGGED1 (JAG1) or NOTCH2, ligand and receptor components of the Notch-signaling pathway, respectively. The detected missense variants are commonly classified as variants of uncertain significance, hindering ALGS diagnosis. To overcome this issue, we have developed a CRISPR\/Cas9-engineered Low-Notch activity (LNA) cells allowing for selective testing of JAG1-NOTCH2 signaling activity. We tested this approach on 9 patients with pediatric hepatopathies with phenotypes ranging from the full clinical ALGS spectrum to isolated neonatal cholestasis and atypical ALGS abnormalities who carried 5\n                    <jats:italic>JAG1<\/jats:italic>\n                    and 3\n                    <jats:italic>NOTCH2<\/jats:italic>\n                    missense variants of interest. Additionally, western blot analyses revealed an effect on protein expression for two\n                    <jats:italic>JAG1<\/jats:italic>\n                    missense variants, one of which had altered glycosylation, potentially indicating pathogenic effects. For this\n                    <jats:italic>JAG1<\/jats:italic>\n                    and one\n                    <jats:italic>NOTCH2 de novo<\/jats:italic>\n                    missense variant, luciferase-based Notch reporter activity was significantly reduced in LNA cells, while no change was observed in commonly used HEK293T, Huh7, or Hep2G cells. These findings allow independent confirmation of recently classified c.53T&gt;G p.(Leu18Arg) in\n                    <jats:italic>JAG1<\/jats:italic>\n                    , and a re-classification of c.1235G&gt;T p.(Cys412Phe) in\n                    <jats:italic>NOTCH2<\/jats:italic>\n                    as likely pathogenic based on ACMG criteria. Collectively, we provide evidence that selective testing of JAG1-NOTCH2 interaction in the newly developed CRISPR-engineered cells, combined with a glycosylation assay, enables robust functional evaluation of ALGS-associated\n                    <jats:italic>JAG1<\/jats:italic>\n                    and\n                    <jats:italic>NOTCH2<\/jats:italic>\n                    variants.\n                  <\/jats:p>","DOI":"10.1007\/s00439-026-02832-7","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T02:19:41Z","timestamp":1776478781000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Improved functional JAG1 and NOTCH2 variant testing in patients with clinical or suspected Alagille syndrome using new low-Notch activity cells"],"prefix":"10.1007","volume":"145","author":[{"given":"Nicole","family":"Buhl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva-Doreen","family":"Pfister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel V.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Turetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eberhard","family":"Lurz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya","family":"Di Donato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Illig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"Skawran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma R.","family":"Andersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Ma\u0161ek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelie","family":"Stalke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"2832_CR1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/s0022-3476(87)80153-1","volume":"110","author":"D Alagille","year":"1987","unstructured":"Alagille D, Estrada A, Hadchouel M, Gautier M, Odi\u00e8vre M, Dommergues JP (1987) Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. 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