Unique variants in the NOTCH2 gene not included in the Genome Aggregation Database (gnomAD) may be responsible for causing Alagille syndrome (ALGS), according to a study recently published in Liver International.

“All NOTCH2 [nonsense-mediated mRNA decay] variants found in gnomAD were not detected in known ALGS patients. And all disease-causing NOTCH2 variants identified in ALGS patients were absent in gnomAD when we re-evaluated NOTCH2 variants reported in medical literature,” the authors wrote.

“So, we hypothesized that an allele frequency that was absent in gnomAD could be considered as a threshold for NOTCH2 pathogenic variants in ALGS.”

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The investigation included 2087 patients from 0 to 20.5 years old with liver pathologies from China. The participants underwent genetic testing to determine JAG1 and NOTCH2 alleles, and correlate them with liver function markers and clinical characteristics previously reported in a database.

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Each patient was classified into 1 of 2 groups: group 1, with 658 individuals, contained those with elevated γ-glutamyltransferase (GGT) either isolated or combined with high alanine aminotransferase and aspartate aminotransferase; and group 2 had 1429 patients and included isolated transaminase elevation, elevated total bilirubin, decreased GGT cholestasis, or increased bile acid, and other abnormalities.

The authors found a total of 35 NOTCH2 mutations in 40 unrelated patients. Group 1 had 16 patients and 14 variants while group 2 had 24 patients and 22 variants. The most frequent mutation type was missense with 31 variants, followed by nonsense and canonical splicing-site, both in 2 cases each. Of all variants, most (22) were novel, 5 extremely rare, and 8 rare, with an allele frequency of 0.001% and 0.01% to 0.001% in the last 2 cases.

The researchers determined a missense variant was pathological whenever at least 3 out of 7 in-silico tools predicted its pathogenicity. Interestingly, pathologic mutations included in gnomAD were similarly distributed among both groups, while those not included mainly were in group 1. Overall, group 1 had 94.44% of the likely-pathogenic (LP) variants.

Finally, when correlating clinical findings with LP and likely benign mutations, 66.67% and 18.18% of the patients were highly linked to extrahepatic phenotypes, respectively. Given these revealing findings, the article concluded that ALGS type 2 is likely if a NOTCH2 mutation is an LP null or missense variant not described in the gnomAD, in the presence of elevated GGT and transaminase plasma levels.


Li Z, Abuduxikuer K, Wang L, et al. Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 by using a large cohort of patients. Liver Int. Published online May 14, 2022. doi:10.1111/liv.15292