JAG1 and THBS2 Mutations in a Child Presenting With Incomplete Alagille Syndrome

To the Editor: Alagille syndrome (ALGS) is an autosomal-dominant multisystem disorder mainly caused by mutations in JAG1 (1,2). Phenotypic expressivity is variable and JAG1 mutations have been found in patients with incomplete ALGS presenting with <3 major features of the syndrome (3,4). Thus, it is also useful to look for a genetic cause in such ALGS-like patients. A genome-wide association study performed in ALGS patients with JAG1 mutations identified a significant locus upstream of the thrombospondin 2 gene (THBS2) (2). THBS2 regulates cell fate and angiogenesis and is expressed in bile ducts in mouse and human livers (2,5). THBS2 modifies JAG1–NOTCH2 interactions in vitro and a THBS2 SNP is associated with cardiovascular diseases (2,6,7). Therefore, THBS2 could be a candidate genetic modifier in ALGS patients, by disrupting JAG1–NOTCH2 signaling (2). So far, THBS2 mutations have not been reported in ALGS patients. We report on a boy who had neonatal cholestasis with elevated serum GGT activity (308 IU/L). At age of 2 months, cholangiography excluded biliary atresia, liver histology showed severe ductopenia, and cardiac ultrasonography a patent foramen ovale. Other target organs were not affected. Genetic analysis identified in the boy a maternal heterozygous JAG1 mutation (NM_000214; c.2828C>T; p.Pro943Leu; ACMG classification: class 3; gnomAD 0.00438%) and a paternal heterozygous THBS2 mutation (NM_003247; c.3296C>T; p.Pro1099Leu; class 2; gnomAD 0.009%) (Fig. 1). His parents were healthy but the mother who transmitted the JAG1 mutation refused any clinical investigation. This observation in a child with incomplete ALGS affecting only the liver and heart, together with data from the literature (2), further suggests that THBS2 could be a modifier gene in some ALGS patients with JAG1 mutations and could play a role in the variable expressivity of this syndrome. The combination of both mutants could explain the incomplete ALGS phenotype in the propositus, by disrupting the JAG1–NOTCH2 signaling. However, a functional evaluation of the interaction of a THBS2 mutant on the Notch signaling pathway as well as the search for THBS2 mutations in patients with ALGS are needed to conclude that THBS2 can be a modifier gene in ALGS.FIGURE 1.: Pedigree and mutation analysis of JAG1 and THBS2 genes in a family. Semifilled symbol indicates heterozygous status for JAG1 mutation (gray color) (p.Pro943Leu) or THBS2 mutation (black color) (p.Pro1099Leu). DNA sequence analysis was performed in each individual reported here, after obtaining informed consent in accordance with protocols for human studies approved by our medical center.ACKNOWLEDGMENTS The family is aware of the intent to publish and agreed to it. We thank the Association Maladie Foie Enfants (AMFE), Malakoff, France, Association “Pour Louis 1000 Foie Merci” (Fournet-Luisans, France), and Fondation Rumsey-Cartier (Genève, Switzerland) for their support.