Alagille syndrome (ALGS) is a rare multisystem disorder most commonly resulting from pathogenic variants in JAG1 and, less frequently, NOTCH2. We evaluated long-term native liver survival (NLS) and overall survival (OS) in a Korean ALGS cohort and compared the genetic characteristics of this cohort with those of the Global ALagille Alliance (GALA) study cohort. We retrospectively reviewed 60 patients with clinically diagnosed ALGS at Seoul National University Hospital. Forty-three patients with genetically confirmed disease were analyzed. Eight patients (18.6%) underwent liver transplantation (median age: 3.9 years), revealing a lower rate than that in the comparator cohort. The estimated NLS percentages at 5, 10, and 18 years were 86.9%, 86.9%, and 76.6%, respectively, exceeding those in previous reports. The corresponding OS rates were 90.2%, 86.9%, and 86.9%, respectively. The following types of JAG1 variants were identified in 41 patients (95.3%): frameshift (34.1%), nonsense (26.8%), missense (24.4%), and splice-site (9.8%) variants and in-frame deletions (4.9%). Compared with the reference group, our cohort exhibited a greater frequency of non-protein-truncating variants (missense variants and in-frame deletions; p = 0.023) and no structural variants (p = 0.043). Two patients (4.7%) carried NOTCH2 nonsense variants. Mortality was significantly higher among patients with frameshift variants compared with patients with non-frameshift variants (4 of 5 deaths; p = 0.035). Conclusion: Compared with the GALA cohort, Korean patients with ALGS exhibited more favorable long-term NLS and a higher proportion of non-protein-truncating JAG1 variants, alongside the absence of structural variants. These findings suggest potential genetic influences and highlight the need for multicenter validation.<Table Float="No" ID="Taba"> <tgroup cols="1"> <colspec align="left" colname="c1" colnum="1" /> <tbody> <row> <entry align="left" colname="c1"> What is Known: • The Global ALagille Alliance (GALA) study reports native liver survival (NLS) rates of 66.8%, 54.4%, and 40.3% at 5, 10, and 18 years, respectively, in patients with Alagille syndrome. • NLS rates are higher among Asians, with unclear genotype–phenotype correlations. </entry> </row> <row> <entry align="left" colname="c1"> What is New: • Compared to the GALA study cohort, the Korean cohort demonstrates superior NLS rates of 86.9%, 86.9%, and 76.6% at 5, 10, and 18 years and a higher frequency of non-truncating JAG1 variants, along with the absence of structural variants. • Protein-truncating variants are associated with higher initial gamma-glutamyl transferase levels, while frameshift variants are associated with reduced overall survival. </entry> </row> </tbody> </tgroup> </Table> Graphical Abstract

Native liver survival and genetic associations in Korean patients with Alagille syndrome

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2026年4月10日

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Shinjie Choi,
Dong-Uk Kim,
Yeji Kim,
Lia Kim,
Jung Ok Shim,
Jin Soo Moon,
Jong Woo Hahn,
Hye Ran Yang,
Ju Young Chang,
Jae Sung Ko

摘要

Alagille syndrome (ALGS) is a rare multisystem disorder most commonly resulting from pathogenic variants in JAG1 and, less frequently, NOTCH2. We evaluated long-term native liver survival (NLS) and overall survival (OS) in a Korean ALGS cohort and compared the genetic characteristics of this cohort with those of the Global ALagille Alliance (GALA) study cohort. We retrospectively reviewed 60 patients with clinically diagnosed ALGS at Seoul National University Hospital. Forty-three patients with genetically confirmed disease were analyzed. Eight patients (18.6%) underwent liver transplantation (median age: 3.9 years), revealing a lower rate than that in the comparator cohort. The estimated NLS percentages at 5, 10, and 18 years were 86.9%, 86.9%, and 76.6%, respectively, exceeding those in previous reports. The corresponding OS rates were 90.2%, 86.9%, and 86.9%, respectively. The following types of JAG1 variants were identified in 41 patients (95.3%): frameshift (34.1%), nonsense (26.8%), missense (24.4%), and splice-site (9.8%) variants and in-frame deletions (4.9%). Compared with the reference group, our cohort exhibited a greater frequency of non-protein-truncating variants (missense variants and in-frame deletions; p = 0.023) and no structural variants (p = 0.043). Two patients (4.7%) carried NOTCH2 nonsense variants. Mortality was significantly higher among patients with frameshift variants compared with patients with non-frameshift variants (4 of 5 deaths; p = 0.035).

Conclusion: Compared with the GALA cohort, Korean patients with ALGS exhibited more favorable long-term NLS and a higher proportion of non-protein-truncating JAG1 variants, alongside the absence of structural variants. These findings suggest potential genetic influences and highlight the need for multicenter validation.

What is Known:

• The Global ALagille Alliance (GALA) study reports native liver survival (NLS) rates of 66.8%, 54.4%, and 40.3% at 5, 10, and 18 years, respectively, in patients with Alagille syndrome.

• NLS rates are higher among Asians, with unclear genotype–phenotype correlations.

What is New:

• Compared to the GALA study cohort, the Korean cohort demonstrates superior NLS rates of 86.9%, 86.9%, and 76.6% at 5, 10, and 18 years and a higher frequency of non-truncating JAG1 variants, along with the absence of structural variants.

• Protein-truncating variants are associated with higher initial gamma-glutamyl transferase levels, while frameshift variants are associated with reduced overall survival.

Graphical Abstract