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. 2022 Aug;42(8):1836-1848.
doi: 10.1111/liv.15292. Epub 2022 May 23.

Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients

Zhong-Die Li  1 , Kuerbanjiang Abuduxikuer  1 , Li Wang  1 , Chen-Zhi Hao  1 , Jing Zhang  2 , Meng-Xuan Wang  2 , Li-Ting Li  1 , Yi-Ling Qiu  1 , Xin-Bao Xie  1 , Yi Lu  1 , Jian-She Wang  1   3
Affiliations

Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients

Zhong-Die Li et al. Liver Int. 2022 Aug.

Abstract

Background and aims: Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed.

Methods: Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2.

Results: Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ-glutamyltransferase (GGT) (p = .041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p = .038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in-silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p = .003). Comparing this to patients with likely benign (LB) variants, the patients with likely-pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p = .0001). Significantly more patients with LP variants had extra-hepatic phenotypes of ALGS compared with those patients with LB variants (p = .0004).

Conclusion: When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in-silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.

Keywords: NOTCH2; Alagille syndrome; rare variants; the interpretation of sequencing variants.

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References

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