Differential prevalence of extrahepatic clinical manifestations in patients with Jagged1 and NOTCH2-associated Alagille syndrome

Vandriel, Shannon M.;et all;Sokal, Etienne M.;et.al.
(2021) 6th World Congress of Pediatric Gastroenterology, Hepatology and Nutrition (WCPGHAN), — Location: Vienne, Autriche (2.June.2021)

Files

GALAJAG1-NOTCH2inALGS_2020_final_SMV1.pdf
  • Open Access
  • Adobe PDF
  • 303.82 KB
Download

Details

Authors
  • Vandriel, Shannon M.
    Author
  • et all
    Author
  • Sokal, Etienne M.orcid-logoUCLouvain
    Author
  • et. al.
Abstract
Background: Alagille syndrome (ALGS) is a phenotypically heterogeneous, autosomal dominant disorder, resulting from pathogenic variants in Jagged1 (JAG1) or NOTCH2. The natural history of liver disease in ALGS is highly variable and there are no known genotypic predictors of hepatic outcomes. The Global ALagille Alliance (GALA) Study Group has ascertained the largest genetically confirmed ALGS cohort to date, permitting exploration of JAG1 and NOTCH2 genotype-phenotype correlations. Method: International multicentre retrospective study of children with ALGS, born between Jan-1997 and Aug-2019 with a pathogenic or likely pathogenic (LP) variant in JAG1 or NOTCH2. Variants were classified according to the American College of Medical Genetics and Genomics criteria. Phenotypic differences were compared between JAG1-and-NOTCH2- ALGS patients and between those with a truncating, non-truncating or structural JAG1 variant, using Chi-square test or Fisher’s exact test. Transplant-free survival (TFS) and overall survival (OS) rates were analyzed using the Kaplan-Meier method. Results: Among 845 genotyped ALGS patients, a pathogenic or LP variant in JAG1 was identified in 97.5% (n=824) and a pathogenic or LP NOTCH2 variant in 2.5% (n=21). Of JAG1 variants, truncating were identified in 73% (n=604), non-truncating in 17% (n=137), and structural variants in 10% (n=83). The phenotypes of JAG1-ALGS patients were clinically indistinguishable with respect to liver involvement, including a history of neonatal cholestasis (NC) (82% vs. 81% vs. 82%, p=0.95) and presence of bile duct paucity (66% vs. 55% vs. 61%, p=0.27). Similarly, no significant differences in the prevalence of extrahepatic manifestations were identified (Table). Ten- and 18-year TFS in ALGS patients with a history of NC and either a truncating (n=473), non-truncating (n=110), or structural JAG1 variant (n=62) were comparable (log-rank, P=0.24). OS rates at 10- and 18-years were ≥88% (log-rank, P=0.08). JAG1-and-NOTCH2 ALGS patients were similar in terms of history of NC (90% vs. 82%, P=0.55), bile duct paucity (54% (n=7/13) vs. 64% (n=202/317, P=0.56), renal anomalies (28% vs. 36%, P=0.50) and vascular anomalies (27% vs. 32%, P=0.79). Those with a NOTCH2 variant were significantly less likely to have characteristic facies (52% vs. 89%, P<0.001), an ECHO-confirmed cardiac anomaly (38% vs. 92%, P<0.001), posterior embryotoxon (13% vs. 52%, P=0.002), or butterfly vertebrae (0% vs. 43%, P<0.001). Ten- and 18-year TFS in patients presenting with NC were comparable between groups (59% and 74%; 49% and 61%, respectively; log-rank P =0.33). OS rates at 10- and 18-years were ≥88% in both groups (log-rank P =0.73). Conclusion: We present the largest, comprehensive genetic analysis in ALGS. No phenotypic differences were observed between ALGS patients with a truncating, non-truncating or structural JAG1 variant. The clinical heterogeneity in ALGS patients harbouring the same pathogenic variant further implicates genetic modifiers in defining the ALGS phenotype. NOTCH2-ALGS patients exhibit significantly reduced penetrance of extrahepatic features in comparison to JAG1-ALGS patients, however the natural history with respect to TFS and OS did not differ between groups.
Affiliations

Citations

  • APA
  • Chicago
  • FWB

Vandriel, S. M., et all, Sokal, E. M., & et al. (2021). Differential prevalence of extrahepatic clinical manifestations in patients with Jagged1 and NOTCH2-associated Alagille syndrome. 6th World Congress of Pediatric Gastroenterology, Hepatology and Nutrition (WCPGHAN), Vienne, Autriche. https://hdl.handle.net/2078.5/108771