{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:59Z","timestamp":1787028239508,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T00:00:00Z","timestamp":1722902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background. Alagille syndrome (ALGS) is a rare autosomal dominant genetic disease caused by pathogenic variants in two genes: Jagged Canonical Notch Ligand 1 (JAG1) and Notch Receptor 2 (NOTCH2). It is characterized by phenotypic variability and incomplete penetrance with multiorgan clinical signs. Methods. Using Next Generation Sequencing (NGS), we analyzed a panel of liver-disease-related genes in a population of 230 patients with cholestasis and hepatopathies. For the rare variants, bioinformatics predictions and pathogenicity classification were performed. Results. We identified eleven rare NOTCH2 variants in 10 patients, two variants being present in the same patient. Ten variants had never been described before in the literature. It was possible to classify only two null variants as pathogenic, whereas the most of variants were missense (8 out of 11) and were classified as uncertain significance variants (USVs). Among patients with ALGS suspicion, two carried null variants, two carried variants predicted to be pathogenic by bioinformatics, one carried a synonymous variant and variants in glycosylation-related genes, and two carried variants predicted as benign in the PEST domain. Conclusions. Our results increased the knowledge about NOTCH2 variants and the related phenotype, allowing us to improve the genetic diagnosis of ALGS.<\/jats:p>","DOI":"10.3390\/genes15081034","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T11:54:19Z","timestamp":1722945259000},"page":"1034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Association of Very Rare NOTCH2 Variants with Clinical Features of Alagille Syndrome"],"prefix":"10.3390","volume":"15","author":[{"given":"Martina","family":"Ferrandino","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5615-298X","authenticated-orcid":false,"given":"Giovanna","family":"Cardiero","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9915-8972","authenticated-orcid":false,"given":"Fabiola","family":"Di Dato","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Mediche Traslazionali, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ylenia","family":"Cerrato","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-3375","authenticated-orcid":false,"given":"Luigi","family":"Vitagliano","sequence":"additional","affiliation":[{"name":"Istituto di Biostrutture e Bioimmagini, CNR, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Mandato","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina, Chirurgia e Odontoiatria \u201cScuola Medica Salernitana\u201d, 84081 Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"Morisco","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Clinica e Chirurgia, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5396-4944","authenticated-orcid":false,"given":"Maria Immacolata","family":"Spagnuolo","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Mediche Traslazionali, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7483-234X","authenticated-orcid":false,"given":"Raffaele","family":"Iorio","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Mediche Traslazionali, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0618-7940","authenticated-orcid":false,"given":"Maria Donata","family":"Di Taranto","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2209-383X","authenticated-orcid":false,"given":"Giuliana","family":"Fortunato","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kamath, B.M., and Loomes, K.M. 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