Brian Murphy, PhD, is a medical/science writer and educator who has written over 300 resource articles about rare diseases. He holds a BS from Georgia Institute of Technology and a PhD from Case Western Reserve University, both in Biomedical Engineering. After graduation, Brian worked as a clinical neural engineer to help restore movement in spinal cord injured patients by reconnecting their brain to their paralyzed muscles using experimental medical devices. In addition to resource pages, Brian has also authored/co-authored several research articles in journals including The Lancet, Journal of Neural Engineering, and PLOS ONE.
Alagille syndrome (ALGS) was first described in 1969 by French hepatologist Daniel Alagille, who found 30 patients with a paucity of bile ducts.1 The disease was also described in a 1973 paper by Watson and Miller who termed the disease “arteriohepatic dysplasia” due to its effects on both the bile ducts and the pulmonary artery.2
Subsequent studies published by Alagille in 19753 and 19874 further expanded the list of symptoms and described the 5 major features of the disease: characteristic facies, chronic cholestasis, embryotoxon, “butterfly” vertebrae, and hypoplasia or stenosis of the peripheral pulmonary artery. These criteria remained the diagnostic tools for ALGS until the discovery in the late 1990s that most patients had chromosomal mutations in the 20p12 band, specifically in the region coding for the Jagged1 (JAG1) transmembrane ligand involved in the Notch signaling pathway of cells.5 The discovery of the molecular mechanism allowed for genetic testing for disease confirmation rather than having to rely fully on symptoms, which vary between patients.
The discovery in the early-6 to mid-2000s7 that mutations in the NOTCH2 gene coding for the Notch 2 transmembrane receptor could also cause ALGS lead to even further genetic testing for confirmation of ALGS.
Genetic Basis of ALGS
Alagille syndrome is predominantly due to mutations in the JAG1 gene (94% to 96%), while a small portion of cases are due to NOTCH2 mutations (2% to 3%).8 There are 694 JAG1 variants and 19 NOTCH2 variants reported in the literature.9
A recent report encompassing 27 years of data from the Children’s Hospital of Philadelphia (CHOP) found that 378 out of 401 patients with ALGS had JAG1 mutations. The most common forms of mutation were frameshift (37%), nonsense (22%), large deletions (13%), missense (13%), and splice site (12%). Of the frameshift mutations, most were caused by either deletions (51%) or duplications (40%). Most of the nonsense mutations were due to single nucleotide substitutions (78%). Single nucleotide substitutions were also the major cause of splice site variants.9 Since the majority of these mutations result in protein truncations while still having similar phenotypes to patients with whole-gene deletions, ALGS is believed to be due to haploinsufficiency.9
The abovementioned CHOP report also found that 10 (2.5%) of the 401 patients had NOTCH2 mutations. Of these patients, 8 had missense mutations while 1 had a splice site and the other had a nonsense mutation. When combined with information from all known NOTCH2 probands, missense mutations are still the most common (13 out of 19; 68%). The authors suggest that this higher rate of ALGS-causing missense mutations could mean that the NOTCH2 gene is less tolerant to missense mutations than the JAG1 gene, where missense mutations only represented 13% of the total types of JAG1 mutations.9
A total of 13 of the 401 patients from the CHOP article did not have mutations in either JAG1 or NOTCH2 despite meeting the ALGS diagnostic criteria of having 3 of the 5 classic characteristics defined for ALGS. The authors conjectured that these patients may have previously undocumented mutations in JAG1 not observed through conventional genetic testing or that they have another genetic disease with overlapping symptoms of ALGS.
Several studies have attempted to quantify a link between genotype and phenotypic presentation and severity but have found wide variability. Even within families who have the same mutations, patients have been found to exhibit different characteristics.10 The large variation in expression suggests other modifying factors and some research has shown possible involvement of the Rumi/Poglut1, SOX9, and THBS2 genes as well as a family of genes called Fringe genes including Lunatic Fringe (LFNG), Radical Fringe (RFNG), and Manic Fringe (MFNG) which affect bile duct growth in murine models.10
Inheritance of ALGS
Alagille syndrome is believed to follow an autosomal dominant inheritance pattern most likely due to haploinsufficiency. Through the analysis of probands and symptom expression in genetically confirmed family members, the penetrance of JAG1 mutations is believed to be 96% while complete penetrance is observed for NOTCH2 mutations.11
Although inheritance is believed to be autosomal dominant, one study did possibly find an autosomal recessive mutation in a single family. The family had 5 children with significant cholestasis with bile duct paucity along with several other ALGS characteristics, including pulmonary valve stenosis, peripheral pulmonary stenosis, and tubular renal acidosis.12 However, genetic testing did not reveal any mutations in JAG1 and a pedigree suggested a recessive inheritance pattern.
Incidence of ALGS
Only 2 studies have attempted to estimate the incidence or birth prevalence of ALGS. The first, published in 1977, was a prospective study that analyzed births in Victoria, Australia between 1963 and 1974.13 The study found 11 of the 790,385 (an incidence of 1:70,000) children born during this period had intrahepatic biliary atresia, the main clinical finding described by Alagille. The variable phenotypes expressed by patients with ALGS and the diagnosis using bile duct paucity would indicate that this estimate is most likely low.
A study in 2003 investigated family members of patients with ALGS and found that 47% of those with JAG1 mutations did not meet the clinical criteria for diagnosis.14 From this study showing that ALGS may be severely underdiagnosed, a publication revised the incidence estimates to the range of between 1:30,000 and 1:50,000.15 The method used to make these estimates from the previous paper was, however, not provided.
- Alagille D, Habib EC, Thomassin N. L’atresie des voies biliaires intrahepatiques avec voies biliaires extrahepatiques permeables chez l’enfant. In: Editions Medicales; Flammarion, Paris. 1969:301-318.
- Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. 1973;48(6):459-466. doi:10.1136/adc.48.6.459
- Alagille D, Odièvre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975;86(1):63-71. doi:10.1016/s0022-3476(75)80706-2
- Alagille D, Estrada A, Hadchouel M, Gautier M, Odièvre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr. 1987;110(2):195-200. doi: 10.1016/s0022-3476(87)80153-1
- Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997;16(3):243-251. doi:10.1038/ng0797-243
- McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development. 2002;129(4):1075-1082.
- McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79(1):169-173. doi:10.1086/505332
- Mitchell E, Gilbert M, Loomes KM. Alagille syndrome. Clin Liver Dis. 2018;22(4):625-641. doi:10.1016/j.cld.2018.06.001
- Gilbert MA, Bauer RC, Rajagopalan R, et al. Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019;40(12):2197-2220. doi:10.1002/humu.23879
- Gilbert MA, Loomes KM. Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts. Transl Gastroenterol Hepatol. 2021;6:22. doi:10.21037/tgh-2020-03
- Spinner NB, Gilbert MA, Loomes KM, Krantz ID. Alagille Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington; 2000 Updated December 12, 2019. Accessed June 16, 2021.
- Dyack S, Cameron M, Otley A, Greer W. An autosomal recessive form of Alagille-like syndrome that is not linked to JAG1. Genet Med. 2007;9(8):544-550. doi:10.1097/gim.0b013e318133a802
- Danks DM, Campbell PE, Jack I, Rogers J, Smith AL. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch Dis Child. 1977;52(5):360-367. doi:10.1136/adc.52.5.360
- Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet. 2003;40(12):891-895. doi:10.1136/jmg.40.12.891
Leonard LD, Chao G, Baker A, Loomes K, Spinner NB. Clinical utility gene card for: Alagille syndrome (ALGS). Eur J Hum Genet. 2014;22(3):435. doi:10.1038/ejhg.2013
Reviewed by Eleni Fitsiou, PhD, on 7/1/2021.