Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Vandriel Shannon M, Li Li-Ting, She Huiyu, Wang Jian-She, Loomes Kathleen M, Piccoli David A, Jankowska Irena, Czubkowski Piotr, Gliwicz-Miedzińska Dorota, D'Antiga Lorenzo, Nicastro Emanuele, Lacaille Florence, Debray Dominique, Sokal Étienne M, Demaret Tanguy, Fawaz Rima L, Nastasio Silvia, Kim Kyung Mo, Oh Seak Hee, Fischler Björn, Arnell Henrik, Larson-Nath Catherine, Hardikar Winita, Shankar Sahana, Sundaram Shikha S, Chaidez Alexander, Bulut Pinar, Calvo Pier Luigi, Kasahara Mureo, Blondet Niviann, Lurz Eberhard, Kavallar Anna-Maria, Gonzales Emmanuel M, Jacquemin Emmanuel, Bouligand Jérôme, Ebel Noelle H, Feinstein Jeffrey A, Siew Susan M, Stormon Michael O, Karpen Saul J, Romero Rene, Jensen M Kyle, Jaramillo Catalina, Squires James E, Bedoyan Sarah M, Kelly Deirdre A, Hartley Jane, Verkade Henkjan J, Lee Way Seah, Lertudomphonwanit Chatmanee, Fischer Ryan T, Lin Henry C, Rock Nathalie, Mozer-Glassberg Yael, Roberts Amin J, Evans Helen M, Karnsakul Wikrom, Nebbia Gabriella, Wolters Victorien M, Valentino Pamela L, Bernabeu Jesus Quintero, Aqul Amal A, Arikan Cigdem, Tamara María Legarda, Busoms Cristina Molera, Sandahl Thomas Damgaard, Indolfi Giuseppe, Zizzo Andréanne N, Zellos Aglaia, Quiros-Tejeira Ruben E, Santos-Silva Ermelinda, Schwarz Kathleen B, Brecelj Jernej, Sanchez Maria Camila, Cavalieri Maria Lorena, Tzivinikos Christos, Wiecek Sabina, Eshun John, Kerkar Nanda, Mujawar Quais, Önal Zerrin, Gonçalves Cristina, Garcia Jennifer, Alam Seema, Jimenez-Rivera Carolina, Bujanda Luis, Thompson Richard J, Hansen Bettina E, Spinner Nancy B, Gilbert Melissa A, Kamath Binita M, Global ALagille Alliance (GALA) Study Group
Аннотация
METHODS: Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants. Previously reported and newly identified NOTCH2 variants were reinterpreted based on disease-specific modifications to the American College of Medical Genetics and Genomics (ACMG) guidelines. The Kaplan-Meier method was utilised to assess native liver survival (NLS) and overall survival (OS) and gene comparisons were made with the log-rank test.
RESULTS: Thirty NOTCH2 variants, including 18 novel variants, were identified and classified in our GALA cohort. Phenotypic analyses revealed a significantly lower incidence of characteristic facies, posterior embryotoxon, cardiac involvement and butterfly vertebrae in individuals with NOTCH2 variants compared to those with JAG1 variants (p < 0.001). No differences were identified in NLS or OS. Review of 61 previously reported NOTCH2 variants resulted in the re-classification of 19 likely pathogenic or pathogenic to VOUS (31.1%) with less than half retaining their originally published classification (34.4%; n = 21).
CONCLUSIONS: We report on a large global study on NOTCH2 genetics and phenotype, which increases the number of reported NOTCH2 variants by 30%. All variants were reclassified using current guidelines, and comparison of the JAG1 and NOTCH2 cohorts demonstrates clear phenotypic divergence between these groups. These data suggest that reliance on classical clinical phenotyping may miss patients with NOTCH2-related disease and supports an inclusive approach to genetic testing.