Abstract

Background: Alagille Syndrome (ALGS) is an autosomal dominant multisystem disorder primarily associated with mutations in the JAG1 gene, exhibiting variable expressivity and incomplete penetrance.

Methods: We describe a Vietnamese family of four members, including two affected siblings and an asymptomatic father, all carrying the same JAG1 c.1456dup (p.Arg486LysfsTer5) mutation.

Results: The siblings exhibited classical ALGS features including neonatal cholestasis, facial dysmorphisms and cardiac defects, while the father remained phenotypically normal. The mother tested negative for the mutation.

Conclusion: This case illustrates the intrafamilial variability and incomplete penetrance of ALGS, emphasizing the role of genetic screening in familial counseling and disease management.

Keywords: Alagille Syndrome; JAG1 Mutation; Frameshift Variant; Intrafamilial Variability; Asymptomatic Carrier; Genetic Counseling

Introduction

Alagille Syndrome (ALGS) is a complex, autosomal dominant multisystem disorder primarily caused by mutations in the JAG1 gene, which encodes a ligand in the Notch signaling pathway critical for embryonic development and cell fate determination across multiple organ systems [1]. The classical phenotype of ALGS includes neonatal cholestasis due to bile duct paucity, congenital heart defects (most commonly peripheral pulmonary stenosis), skeletal anomalies such as butterfly vertebrae, distinctive facial features and ocular findings such as posterior embryotoxon [2].

A defining characteristic of ALGS is its highly variable expressivity and incomplete penetrance, even among individuals carrying the same pathogenic variant within a single family [3]. This phenotypic diversity complicates diagnosis, management and genetic counseling. In this report, we describe a Vietnamese family harboring a novel JAG1 frameshift mutation. Notably, two affected siblings display classical ALGS features, while their father-who carries the same pathogenic variant-remains clinically asymptomatic. This case contributes to the understanding of intrafamilial variability and supports the critical role of comprehensive genetic evaluation and family screening.

Case Presentation

Family History and Background

The family originates from Long An province, Vietnam, comprising four individuals: two affected daughters, a clinically unaffected father and a mother without the JAG1 mutation. No prior family history of liver, cardiac or skeletal anomalies was reported before the diagnosis (Fig. 1, Table 1).

Patient 1 (Older Sister)

A term-born female (birth weight: 2.5 kg) presented at 3 months of age with persistent jaundice and characteristic facial features. Laboratory findings showed elevated liver enzymes (AST 442.57 U/L, ALT 526.37 U/L, GGT 895.46 U/L) and hyperbilirubinemia (total bilirubin 171.8 μmol/L, direct 99.5 μmol/L). Echocardiography revealed mild bilateral pulmonary artery branch stenosis and spinal radiographs showed a butterfly vertebra at T7. Genetic testing identified a heterozygous JAG1 c.1456dup mutation. She received treatment with ursodeoxycholic acid, fat-soluble vitamins, calcium and vitamin D. At her latest follow-up in March 2025, bilirubin levels had normalized, although GGT remained elevated (GGT 1073.69 U/L).

Patient 2 (Younger Sister)

A preterm-born female (36 weeks gestation, 2.3 kg) presented with jaundice and anemia. Laboratory investigations revealed AST 485.17 U/L, ALT 448.95 U/L, total bilirubin 184 μmol/L, direct 110 μmol/L and GGT 344.89 U/L. Echocardiography demonstrated pulmonary artery stenosis and a patent ductus arteriosus. She experienced recurrent episodes of anemia requiring multiple blood transfusions.

She carried the same JAG1 c.1456dup mutation. Management included ursodeoxycholic acid, multivitamins, calcium, iron supplementation and vitamin C. At her most recent evaluation, hyperbilirubinemia persisted (total bilirubin 287.63 μmol/L, direct 160 μmol/L), although anemia had improved.

Father

The father tested positive for the heterozygous JAG1 c.1456dup mutation but exhibited no clinical manifestations. Comprehensive assessments-including liver function tests, echocardiography, skeletal imaging and ophthalmologic examination-were within normal limits. He remains asymptomatic to date.

Mother

Genetic screening revealed no JAG1 mutation. The mother is phenotypically normal with no signs of liver, cardiac, skeletal or ocular involvement.

Figure 1: Genetic analysis result. Sanger sequencing demonstrating the heterozygous frameshift mutation c.1456dup (p.Arg486LysfsTer5) in exon 12 of the JAG1 gene in both daughters and the asymptomatic father.