Alagille syndrome

Mendelian MONDO:0007318 Pathograph 44 Show in embeddings browser hereditary disease cholestatic liver disease

Alagille syndrome is an autosomal dominant multisystem developmental disorder caused primarily by heterozygous pathogenic variants in JAG1 and less often NOTCH2. The core mechanism is impaired Notch signaling during embryogenesis, which disrupts bile duct, cardiovascular, ocular, skeletal, renal, and facial development. Clinically, the syndrome is characterized by paucity of interlobular bile ducts with cholestasis, congenital heart disease particularly involving the pulmonary arteries, posterior embryotoxon, butterfly vertebrae, and variable extrahepatic involvement.

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5
Mappings
1
Definitions
1
Inheritance
6
Pathophys.
1
Histopath.
31
Phenotypes
44
Pathograph
2
Genes
6
Medical Actions
3
Subtypes
2
Differentials
1
Datasets
2
Trials
5
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0007318 Alagille syndrome
skos:exactMatch ORPHA:52 ORPHA:52: CONSISTENT
Orphanet lists MONDO:0007318 as an exact cross-reference for Alagille syndrome.
MONDO:0016862 Alagille syndrome due to a JAG1 point mutation Not Yet Curated
skos:narrowMatch MONDO
MONDO:0016862 is_a the MONDO:0007318 anchor of this entry and is defined as its JAG1 subtype (intersection_of RO:0004003 HGNC:6188). This entry curates JAG1 (hgnc:6188) alongside NOTCH2 (hgnc:7882), so the JAG1 child term is covered here. narrowMatch rather than exactMatch because the anchor also subsumes the NOTCH2 form and the JAG1 whole-gene deletions that this child term, being restricted to point mutations, excludes.
MONDO:0016861 Alagille syndrome due to 20p12 microdeletion Not Yet Curated
skos:narrowMatch MONDO
MONDO:0016861 is a JAG1-containing 20p12 deletion subtype of the broader MONDO:0007318 disease curated in this entry.
MONDO:0012439 Alagille syndrome due to a NOTCH2 point mutation Not Yet Curated
skos:narrowMatch MONDO
MONDO:0012439 is the NOTCH2 point-variant subtype of the broader MONDO:0007318 disease curated in this entry.
ICD-10-CM
ICD10CM:Q44.7 Other congenital malformations of liver
skos:narrowMatch ORPHA:52 ORPHA:52: CONSISTENT
Orphanet lists ICD-10 Q44.7 as a narrower cross-reference for Alagille syndrome.
📘

Definitions

1
Orphanet disease definition
Orphanet defines Alagille syndrome as a rare syndrome variably characterized by chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, vertebrae segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys.
CASE_DEFINITION
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"A rare syndrome variably characterized by chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, vertebrae segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys."
Orphanet's definition supports the multisystem developmental framing of this entry.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Alagille syndrome is classically inherited in an autosomal dominant manner, although penetrance and organ involvement are highly variable.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:30266153 SUPPORT Human Clinical
"Alagille syndrome is a complex multisystem autosomal dominant disorder with a wide variability in penetrance of clinical features."
This review directly states the canonical inheritance pattern.
ORPHA:52 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for Alagille syndrome.
PMID:20301450 SUPPORT Human Clinical
"Offspring of an individual with ALGS have a 50% chance of inheriting the JAG1 or NOTCH2 pathogenic variant."
GeneReviews states the recurrence risk for autosomal dominant transmission.
◆

Subtypes

3
JAG1 point-variant ALGS MONDO:0016862
JAG1 hgnc:6188 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in JAG1 (hgnc:6188). hgnc:6188 is a gene from the HUGO Gene Nomenclature Committee.
Alagille syndrome caused by a pathogenic JAG1 sequence variant.
Show evidence (1 reference)
PMID:9207788 SUPPORT Human Clinical
"We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome."
The original gene-discovery study directly supports a JAG1 coding-variant subtype.
20p12 deletion ALGS MONDO:0016861
JAG1 hgnc:6188 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in JAG1 (hgnc:6188). hgnc:6188 is a gene from the HUGO Gene Nomenclature Committee.
Alagille syndrome caused by a 20p12 deletion encompassing JAG1, sometimes with additional contiguous-gene features.
Show evidence (1 reference)
PMID:9207788 SUPPORT Human Clinical
"Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome"
The original gene-discovery study directly supports the JAG1-containing deletion subtype.
NOTCH2 point-variant ALGS MONDO:0012439
NOTCH2 hgnc:7882 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in NOTCH2 (hgnc:7882). hgnc:7882 is a gene from the HUGO Gene Nomenclature Committee.
Alagille syndrome caused by a pathogenic NOTCH2 variant; classical facies, posterior embryotoxon, cardiac involvement, and butterfly vertebrae occur less often than in JAG1-associated disease.
Show evidence (1 reference)
PMID:40742203 SUPPORT Human Clinical
"Phenotypic analyses revealed a significantly lower incidence of characteristic facies, posterior embryotoxon, cardiac involvement and butterfly vertebrae in individuals with NOTCH2 variants compared to those with JAG1 variants"
The GALA cohort demonstrates clinically important divergence of the NOTCH2-associated subtype.
⚙

Pathophysiology

6
JAG1 haploinsufficiency
Loss-of-function JAG1 variants and deletions reduce functional Jagged1 dosage; JAG1 haploinsufficiency is the established mechanism for most Alagille syndrome.
JAG1 hgnc:6188 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAG1 (hgnc:6188). hgnc:6188 is a gene from the HUGO Gene Nomenclature Committee.
Notch signaling pathway GO:0007219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Attenuated portal vascular-to-cholangiocyte Notch signaling Reduced Jagged1 dosage weakens developmental cell-cell Notch signaling around portal vessels.
Cardiovascular developmental defects Impaired Notch signaling perturbs cardiac and vascular morphogenesis.
Butterfly vertebrae
Posterior embryotoxon
Peculiar facies
Pointed chin
Frontal bossing
Protruding ear
Long nose
Vertebral segmentation defect
Spina bifida occulta
Telangiectasia of the skin
Renal hypoplasia/aplasia
Abnormal renal morphology
Intrauterine growth retardation
Cryptorchidism
Strabismus
Mild intellectual disability
Abnormality of chorioretinal pigmentation
Show evidence (2 references)
PMID:40742203 SUPPORT Human Clinical
"JAG1 variants cause disease through a mechanism of haploinsufficiency, but the mechanism for NOTCH2 variants is not completely understood"
The 2025 GALA analysis distinguishes established JAG1 haploinsufficiency from the unresolved NOTCH2 mechanism.
PMID:9207788 SUPPORT Human Clinical
"We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome."
The landmark discovery paper directly supports JAG1 as the causal gene in Alagille syndrome.
NOTCH2 pathogenic variant
Mechanism confidence: Provisional
A minority of genetically confirmed cases carry pathogenic NOTCH2 variants. The causal relationship is definitive, but unlike JAG1, the variant-level molecular mechanism is not yet completely understood.
NOTCH2 hgnc:7882 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOTCH2 (hgnc:7882). hgnc:7882 is a gene from the HUGO Gene Nomenclature Committee.
Notch signaling pathway GO:0007219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Attenuated portal vascular-to-cholangiocyte Notch signaling Pathogenic NOTCH2 variants are expected to impair the receptor arm of the same developmental signaling axis, although their exact molecular effects vary.
Show evidence (1 reference)
PMID:40742203 SUPPORT Human Clinical
"Disease-causing variants are primarily identified in Jagged1 (JAG1), with fewer reported in NOTCH2."
The GALA cohort confirms NOTCH2-associated Alagille syndrome while emphasizing its rarity.
Attenuated portal vascular-to-cholangiocyte Notch signaling
JAG1-expressing immature portal vascular smooth muscle cells signal to adjacent cholangiocyte progenitors. Loss of JAG1 at this interface attenuates Notch-dependent cholangiocyte differentiation and bile-duct formation.
portal vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves portal vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology. intrahepatic cholangiocyte CL:0002538 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intrahepatic cholangiocyte (CL:0002538). CL:0002538 is a cell type from the Cell Ontology.
Notch signaling pathway GO:0007219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Abnormal bile duct morphogenesis Reduced portal vascular Jagged1-Notch signaling impairs cholangiocyte differentiation and duct assembly.
Show evidence (1 reference)
PMID:39198465 SUPPORT In Vitro
"Knocking out JAG1 in hiPSC-BV significantly attenuates bile duct formation, highlighting BVLO potential as a model for Alagille syndrome, a congenital biliary disease."
Human iPSC vascularized liver organoids directly support a JAG1-dependent vascular-to-biliary developmental interface.
Abnormal bile duct morphogenesis
Developmental failure of normal intrahepatic bile duct formation produces paucity of interlobular bile ducts, the core hepatic lesion of Alagille syndrome.
intrahepatic cholangiocyte CL:0002538 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intrahepatic cholangiocyte (CL:0002538). CL:0002538 is a cell type from the Cell Ontology.
intrahepatic bile duct development GO:0035622 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intrahepatic bile duct development (GO:0035622). GO:0035622 is a biological process from the Gene Ontology. ↓ DECREASED
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cholestatic liver disease Bile duct paucity causes impaired bile flow and chronic cholestasis.
Reduced number of intrahepatic bile ducts
Cholestasis
Hepatomegaly
Show evidence (1 reference)
PMID:12420916 SUPPORT Human Clinical
"Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts"
This directly supports bile duct paucity as the defining hepatic developmental lesion.
Cholestatic liver disease
Bile duct paucity results in chronic cholestatic liver disease, producing jaundice, pruritus, fat-soluble vitamin deficiency, and progressive hepatic morbidity in severe cases.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pruritus Chronic cholestasis drives severe itching and symptomatic burden.
Xanthomatosis Retention of cholesterol-rich lipids in severe cholestasis promotes cutaneous xanthomas.
Portal hypertension Progressive liver injury can culminate in clinically evident portal hypertension.
Failure to thrive Cholestatic malabsorption and fat-soluble vitamin deficiency impair growth.
Delayed puberty Chronic cholestatic malnutrition and growth impairment can delay pubertal development.
Show evidence (1 reference)
PMID:35868679 SUPPORT Human Clinical
"Alagille syndrome (ALGS) is a complex heterogenous disease with a wide array of clinical manifestations in association with cholestatic liver disease."
This review directly identifies cholestatic liver disease as a central downstream consequence.
Cardiovascular developmental defects
Notch pathway dysfunction disrupts embryonic cardiovascular development, contributing to pulmonary artery stenosis and other congenital cardiac and vascular abnormalities.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Peripheral pulmonary artery stenosis
Tetralogy of Fallot
Atrial septal defect
Renal artery stenosis Systemic developmental arteriopathy includes stenosis of the renal arteries.
Show evidence (2 references)
PMID:30266153 SUPPORT Human Clinical
"Liver disease is a major cause of morbidity in this population, whereas cardiac and vascular involvement accounts for most of the mortality."
This supports a major and clinically consequential cardiovascular developmental branch in Alagille syndrome.
PMID:39446153 SUPPORT Model Organism
"Notch signalling is essential for vascular morphogenesis and remodelling in mice."
This review supports the developmental vascular role of Notch while correctly limiting the direct experimental basis to mice.
✶

Histopathology

1
Paucity of interlobular bile ducts
Reduced interlobular bile ducts on liver biopsy are the characteristic hepatic histopathologic lesion, although a molecular diagnosis may establish Alagille syndrome without biopsy.
Show evidence (1 reference)
PMID:20301450 SUPPORT Human Clinical
"The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis"
GeneReviews directly identifies bile duct paucity as the characteristic biopsy finding.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Alagille syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

31
Cardiovascular 8
Peripheral pulmonary artery stenosis FREQUENT HP:0004969 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral pulmonary artery stenosis (HP:0004969). HP:0004969 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:12427653 SUPPORT Human Clinical
"The most common abnormality was stenosis/hypoplasia of the branch pulmonary arteries (PAs), which was documented by imaging (n=111) or inferred from a peripheral pulmonary stenosis murmur (n=41) in 76% of subjects."
McElhinney et al. (n=200) found branch PA stenosis in 76% of Alagille patients, firmly in the FREQUENT band.
PMID:12420916 SUPPORT Human Clinical
"Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis"
This supports peripheral pulmonary arterial stenosis as a classic major feature.
ORPHA:52 SUPPORT Other
"HP:0004969 | Peripheral pulmonary artery stenosis | Occasional (29-5%)"
Orphanet lists this as occasional, but clinical cohort data (76% in McElhinney 2002) supports FREQUENT. The Orphanet frequency annotation appears discordant with the literature for this phenotype.
Tetralogy of Fallot OCCASIONAL HP:0001636 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetralogy of Fallot (HP:0001636). HP:0001636 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12427653 SUPPORT Human Clinical
"Tetralogy of Fallot was present in 23 subjects and was accompanied by pulmonary atresia in 8."
McElhinney et al. found tetralogy of Fallot in 23/200 (11.5%) Alagille patients, placing it in the OCCASIONAL frequency band.
Portal hypertension FREQUENT HP:0001409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Portal hypertension (HP:0001409), qualified as course progressive. HP:0001409 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Sequelae: Splenomegaly
Show evidence (1 reference)
PMID:39446153 SUPPORT Human Clinical
"the cumulative incidences of portal hypertension and liver transplantation are 66% and 50% respectively at 18 years of age."
The cumulative incidence of portal hypertension is in the FREQUENT band by age 18.
Renal artery stenosis HP:0001920 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal artery stenosis (HP:0001920). HP:0001920 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hypertension
Show evidence (1 reference)
PMID:39446153 SUPPORT Human Clinical
"Renal artery stenosis and mid aortic syndrome have also frequently been reported, often associated with hypertension and stenosis and/or aneurysm of other large arteries."
This directly supports renal artery stenosis within the Alagille vascular phenotype.
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301450 SUPPORT Human Clinical
"Renal abnormalities, growth failure, behavioral differences, splenomegaly, retinal changes, and vascular abnormalities may also occur."
GeneReviews includes splenomegaly among recognized manifestations.
Telangiectasia of the skin FREQUENT HP:0100585 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Telangiectasia of the skin (HP:0100585). HP:0100585 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0100585 | Telangiectasia of the skin | Frequent (79-30%)"
Orphanet phenotype table lists skin telangiectasia as frequent in Alagille syndrome.
Hypertension OCCASIONAL HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0000822 | Hypertension | Occasional (29-5%)"
Orphanet phenotype table lists hypertension as occasional in Alagille syndrome.
Atrial septal defect OCCASIONAL HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0001631 | Atrial septal defect | Occasional (29-5%)"
Orphanet phenotype table lists atrial septal defect as occasional in Alagille syndrome.
Digestive 3
Cholestasis VERY_FREQUENT HP:0001396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cholestasis (HP:0001396). HP:0001396 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12420916 SUPPORT Human Clinical
"Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts"
This directly supports cholestasis as a defining syndrome feature.
ORPHA:52 SUPPORT Other
"HP:0001396 | Cholestasis | Very frequent (99-80%)"
Orphanet phenotype table lists cholestasis as very frequent in Alagille syndrome.
Hepatomegaly VERY_FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0002240 | Hepatomegaly | Very frequent (99-80%)"
Orphanet phenotype table lists hepatomegaly as very frequent in Alagille syndrome.
Reduced number of intrahepatic bile ducts VERY_FREQUENT HP:0006571 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced number of intrahepatic bile ducts (HP:0006571). HP:0006571 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:52 SUPPORT Other
"HP:0006571 | Reduced number of intrahepatic bile ducts | Very frequent (99-80%)"
Orphanet phenotype table lists reduced intrahepatic bile ducts as very frequent.
PMID:12420916 SUPPORT Human Clinical
"chronic cholestasis owing to paucity of interlobular bile ducts"
This directly supports bile duct paucity as a defining feature.
Ear 1
Protruding ear FREQUENT HP:0000411 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protruding ear (HP:0000411). HP:0000411 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0000411 | Protruding ear | Frequent (79-30%)"
Orphanet phenotype table lists protruding ear as frequent in Alagille syndrome.
Endocrine 1
Delayed puberty OCCASIONAL HP:0000823 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed puberty (HP:0000823). HP:0000823 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0000823 | Delayed puberty | Occasional (29-5%)"
Orphanet phenotype table lists delayed puberty as occasional in Alagille syndrome.
Eye 3
Posterior embryotoxon FREQUENT HP:0000627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posterior embryotoxon (HP:0000627). HP:0000627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12420916 SUPPORT Human Clinical
"Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral arch defect; posterior embryotoxon"
This directly supports posterior embryotoxon as a defining ocular feature.
PMID:39446153 SUPPORT Human Clinical
"Posterior embryotoxon is present in 51%, and butterfly vertebrae in 44% of patients"
The 51% estimate supports the FREQUENT band.
Abnormality of chorioretinal pigmentation HP:0007661 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of chorioretinal pigmentation (HP:0007661). HP:0007661 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301450 SUPPORT Human Clinical
"Renal abnormalities, growth failure, behavioral differences, splenomegaly, retinal changes, and vascular abnormalities may also occur."
GeneReviews supports retinal changes as a recognized extrahepatic manifestation.
Strabismus OCCASIONAL HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0000486 | Strabismus | Occasional (29-5%)"
Orphanet phenotype table lists strabismus as occasional in Alagille syndrome.
Genitourinary 3
Abnormal renal morphology FREQUENT HP:0012210 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal renal morphology (HP:0012210). HP:0012210 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39446153 SUPPORT Human Clinical
"Kidney involvement is present in 38% of patients, and can reveal the disease."
The reported 38% prevalence places broad renal involvement in the FREQUENT band.
Renal hypoplasia/aplasia OCCASIONAL HP:0008678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypoplasia/aplasia (HP:0008678). HP:0008678 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0008678 | Renal hypoplasia/aplasia | Occasional (29-5%)"
Orphanet phenotype table lists renal hypoplasia/aplasia as occasional.
Cryptorchidism OCCASIONAL HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0000028 | Cryptorchidism | Occasional (29-5%)"
Orphanet phenotype table lists cryptorchidism as occasional in Alagille syndrome.
Head and Neck 4
Peculiar facies FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12420916 SUPPORT Human Clinical
"Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral arch defect; posterior embryotoxon and peculiar facies."
This directly supports characteristic facies as a classic feature of Alagille syndrome.
ORPHA:52 SUPPORT Other
"HP:0000280 | Coarse facial features | Frequent (79-30%)"
The FREQUENT band is carried over from Orphanet's coarse-facial-features row as a quantified component of the broader characteristic facies.
Pointed chin FREQUENT HP:0000307 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pointed chin (HP:0000307). HP:0000307 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0000307 | Pointed chin | Frequent (79-30%)"
Orphanet phenotype table lists pointed chin as frequent in Alagille syndrome.
Frontal bossing FREQUENT HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0002007 | Frontal bossing | Frequent (79-30%)"
Orphanet phenotype table lists frontal bossing as frequent in Alagille syndrome.
Long nose FREQUENT HP:0003189 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long nose (HP:0003189). HP:0003189 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0003189 | Long nose | Frequent (79-30%)"
Orphanet phenotype table lists long nose as frequent in Alagille syndrome.
Integument 2
Pruritus FREQUENT HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34215014 SUPPORT Human Clinical
"Medical management is supportive, focusing on clinical manifestations of disease, with liver transplant indicated for severe pruritus"
This supports severe pruritus as a clinically important hepatic symptom.
PMID:39446153 SUPPORT Human Clinical
"neonatal cholestasis occurs in 85% of cases, pruritus in 74%, xanthomas in 24% of cases"
The review provides a quantitative estimate placing pruritus in the FREQUENT band.
Xanthomatosis OCCASIONAL HP:0000991 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Xanthomatosis (HP:0000991). HP:0000991 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39446153 SUPPORT Human Clinical
"neonatal cholestasis occurs in 85% of cases, pruritus in 74%, xanthomas in 24% of cases"
A 24% estimate places xanthomas in the OCCASIONAL band.
Musculoskeletal 2
Butterfly vertebrae FREQUENT HP:0003316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Butterfly vertebrae (HP:0003316). HP:0003316 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12420916 SUPPORT Human Clinical
"Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral arch defect"
This directly supports butterfly vertebrae as a core skeletal feature.
PMID:39446153 SUPPORT Human Clinical
"Posterior embryotoxon is present in 51%, and butterfly vertebrae in 44% of patients"
The 44% estimate supports the FREQUENT band.
Vertebral segmentation defect FREQUENT HP:0003422 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertebral segmentation defect (HP:0003422). HP:0003422 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0003422 | Vertebral segmentation defect | Frequent (79-30%)"
Orphanet phenotype table lists vertebral segmentation defects as frequent.
Nervous System 2
Spina bifida occulta FREQUENT HP:0003298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spina bifida occulta (HP:0003298). HP:0003298 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0003298 | Spina bifida occulta | Frequent (79-30%)"
Orphanet phenotype table lists spina bifida occulta as frequent in Alagille syndrome.
Mild intellectual disability OCCASIONAL HP:0001256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild intellectual disability (HP:0001256). HP:0001256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0001256 | Intellectual disability, mild | Occasional (29-5%)"
Orphanet phenotype table lists mild intellectual disability as occasional.
Growth 2
Failure to thrive VERY_FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0001508 | Failure to thrive | Very frequent (99-80%)"
Orphanet phenotype table lists failure to thrive as very frequent in Alagille syndrome.
Intrauterine growth retardation FREQUENT HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"HP:0001511 | Intrauterine growth retardation | Frequent (79-30%)"
Orphanet phenotype table lists IUGR as frequent in Alagille syndrome.
🧬

Genetic Associations

2
JAG1 (Causal haploinsufficiency or pathogenic heterozygous variant)
Gene: JAG1 hgnc:6188 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is JAG1 (hgnc:6188). hgnc:6188 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:40742203 SUPPORT Human Clinical
"Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants."
This large molecularly defined cohort directly supports JAG1 as the predominant causal gene.
NOTCH2 (Causal heterozygous variant)
Gene: NOTCH2 hgnc:7882 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NOTCH2 (hgnc:7882). hgnc:7882 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:40742203 SUPPORT Human Clinical
"Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants."
This molecularly defined cohort directly supports NOTCH2 as a rare causal gene.
CGGV:assertion_044f1413-e1cd-4212-9e9a-a4d9c66c08dc-2025-02-26T170000.000Z SUPPORT Other
"NOTCH2 | HGNC:7882 | Alagille syndrome | MONDO:0007318 | AD | Definitive"
ClinGen classifies the NOTCH2-Alagille syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
🗃️

External Assertions

1
Orphanet Alagille syndrome record
Orphanet Structured disease record ORPHA:52
Orphanet structured record for Alagille syndrome, including curated cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA, and UMLS identifiers.
Show evidence (4 references)
ORPHA:52 SUPPORT Other
"MONDO:0007318 | Exact"
The Orphanet cross-reference table exactly maps ORPHA:52 to MONDO:0007318.
ORPHA:52 SUPPORT Other
"ICD-10:Q44.7 | Narrower"
The Orphanet cross-reference table maps ORPHA:52 to ICD-10 Q44.7 as a narrower match.
ORPHA:52 SUPPORT Other
"OMIM:118450 | Exact"
The Orphanet cross-reference table exactly maps ORPHA:52 to OMIM 118450.
+ 1 more reference
💊

Medical Actions

6
Maralixibat
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: maralixibat NCIT:C170148 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses maralixibat (NCIT:C170148). NCIT:C170148 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Ileal bile acid transporter inhibition with maralixibat is used to reduce cholestatic pruritus in Alagille syndrome.
Target Phenotypes: Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology. Cholestasis HP:0001396 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cholestasis (HP:0001396). HP:0001396 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34755627 SUPPORT Human Clinical
"In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect."
The disease-specific randomized withdrawal period directly supports durable reductions in serum bile acids and pruritus.
Odevixibat
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: odevixibat NCIT:C166598 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses odevixibat (NCIT:C166598). NCIT:C166598 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Ileal bile acid transporter inhibition with odevixibat reduces serum bile acids and cholestatic pruritus in Alagille syndrome.
Target Phenotypes: Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology. Cholestasis HP:0001396 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cholestasis (HP:0001396). HP:0001396 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38670135 SUPPORT Human Clinical
"Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome."
The phase 3 ASSERT trial directly supports odevixibat for pruritus and serum bile-acid reduction.
JAG1-upregulating antisense oligonucleotide (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Antisense oligonucleotide
RNA target: JAG1 hgnc:6188 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of JAG1 (hgnc:6188). hgnc:6188 is a gene from the HUGO Gene Nomenclature Committee. JAG1 mRNA upstream open reading frame
Experimental ASOs targeting a JAG1 mRNA upstream open reading frame increase JAG1 translation; efficacy has so far been demonstrated only in cells and a Jag1-haploinsufficient mouse model. The abstract reports multiple translational mechanisms without identifying the optimized ASO's specific mechanism, so an oligonucleotide_mechanism enum is not asserted.
Mechanism Target:
ACTIVATES JAG1 haploinsufficiency — The ASO is designed to increase translation from the remaining functional JAG1 allele.
Show evidence (1 reference)
PMID:40980686 SUPPORT In Vitro
"certain ASOs targeting the upstream open reading frame (uORF) increased JAG1 protein levels"
The experiment directly supports activation of residual JAG1 translation as the treatment mechanism.
Show evidence (2 references)
PMID:40980686 SUPPORT In Vitro
"We found that certain ASOs targeting the upstream open reading frame (uORF) increased JAG1 protein levels in various cell lines and ALGS patient-derived cells."
Cell experiments support the intended translational-upregulation mechanism.
PMID:40980686 SUPPORT Model Organism
"When newborn Jag1 +/- mice were treated with ASO, improved bile duct development was observed, along with trends of reduced plasma bile acids, bilirubin, and triglyceride levels, implying improved liver function."
Mouse treatment data provide preclinical evidence while not asserting human efficacy.
Liver transplantation
Action: liver transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is liver transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. Ontology label: Liver Transplantation NCIT:C15271
Platform: Surgery
Liver transplantation is used for severe hepatic disease, growth failure, portal hypertension, or refractory pruritus.
Target Phenotypes: Cholestasis HP:0001396 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cholestasis (HP:0001396). HP:0001396 is a phenotype from the Human Phenotype Ontology. Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34215014 SUPPORT Human Clinical
"liver transplant indicated for severe pruritus, liver synthetic dysfunction, portal hypertension, bone fractures, and/or growth failure."
This directly supports liver transplantation for severe hepatic manifestations.
Nutritional and fat-soluble vitamin support
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Calorie optimization and replacement of fat-soluble vitamins address growth failure and malabsorption associated with chronic cholestasis.
Target Phenotypes: Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301450 SUPPORT Other
"optimized nutrition and replacement of fat-soluble vitamins as needed"
GeneReviews recommends nutritional optimization and vitamin replacement as supportive management.
Activity and alcohol risk counseling
Action: Behavioral CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Behavioral Counseling (NCIT:C181743). NCIT:C181743 is a clinical intervention from the NCI Thesaurus. NCIT:C181743
Platform: Behavioral / lifestyle
Counsel patients to avoid contact sports and, when liver disease is present, alcohol consumption.
Show evidence (1 reference)
PMID:20301450 SUPPORT Other
"Agents/circumstances to avoid: Contact sports; alcohol consumption if liver disease is present."
GeneReviews explicitly lists these risk-reduction recommendations.
🔬

Biochemical Markers

2
Elevated serum bile acids (INCREASED)
Context: Cholestasis commonly produces high serum bile-acid concentrations and the level is a pharmacodynamic treatment readout.
Show evidence (1 reference)
PMID:38670135 SUPPORT Human Clinical
"cholestasis-associated clinical features can include high serum bile acids and severe pruritus"
The ASSERT trial identifies high serum bile acids as a disease-associated biochemical feature.
Total bilirubin in infancy (INCREASED)
Context: Total bilirubin between six and twelve months is a prognostic biomarker for portal hypertension and native-liver survival.
Reference Ranges
– mg/dL (children with Alagille syndrome, age 6-12 months)
Lower hepatic-risk band (–5.0 mg/dL) Intermediate hepatic-risk band (5.0–10.0 mg/dL) High hepatic-risk band (10.0– mg/dL)
Lower hepatic-risk band: Median total bilirubin below 5.0 mg/dL was the reference group and was associated with better hepatic outcomes.
Intermediate hepatic-risk band: Median total bilirubin from 5.0 to below 10.0 mg/dL was associated with a 4.8-fold increased transplantation risk relative to below 5.0 mg/dL.
High hepatic-risk band: Median total bilirubin above 10.0 mg/dL was associated with a 15.6-fold increased transplantation risk relative to below 5.0 mg/dL.
Prognostic bands for later clinically evident portal hypertension and liver transplantation; these are not general laboratory reference intervals.
Show evidence (1 reference)
PMID:36036223 SUPPORT Human Clinical
"Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl."
GALA provides directly computable infant total-bilirubin prognostic tiers.
Show evidence (1 reference)
PMID:36036223 SUPPORT Human Clinical
"A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes."
The international GALA cohort supports infant total bilirubin as an objective prognostic biomarker.
🔬

Diagnosis

3
Molecular genetic testing
Diagnostic confirmation is achieved by identifying a pathogenic JAG1 or NOTCH2 variant.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Heterozygous pathogenic variant in JAG1 or NOTCH2 supports the diagnosis.
Show evidence (1 reference)
PMID:20301450 SUPPORT Human Clinical
"The diagnosis of ALGS is established in a proband who meets clinical diagnostic criteria and/or has a heterozygous pathogenic variant in JAG1 or NOTCH2 identified by molecular genetic testing."
GeneReviews directly supports clinical criteria and JAG1/NOTCH2 molecular testing as diagnostic routes.
Liver biopsy
Liver biopsy can document paucity of interlobular bile ducts in patients with hepatic-predominant presentations.
biopsy of liver NCIT:C51677 NCI Thesaurus (NCIT)
Results: Paucity of interlobular bile ducts supports the hepatic diagnosis.
Show evidence (1 reference)
PMID:20301450 SUPPORT Human Clinical
"The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis"
GeneReviews directly links liver biopsy with the diagnostic finding of bile duct paucity.
Hepatocellular carcinoma surveillance
Serum alpha-fetoprotein and liver ultrasound are used every six months for hepatocellular carcinoma surveillance.
liver ultrasound surveillance NCIT:C17230 NCI Thesaurus (NCIT)
Results: A new focal liver lesion or rising alpha-fetoprotein requires diagnostic evaluation.
Show evidence (1 reference)
PMID:20301450 SUPPORT Other
"serum alpha-fetoprotein and liver ultrasound every six months"
GeneReviews gives the disease-specific hepatocellular carcinoma surveillance interval and modalities.
📈

Progression

2
Neonatal and infantile cholestasis
Age: Infancy
Liver disease often presents with cholestasis early in life, but severity is highly variable.
Show evidence (1 reference)
PMID:39446153 SUPPORT Human Clinical
"neonatal cholestasis occurs in 85% of cases"
This supports early hepatic presentation in most clinically recognized cases.
Progressive liver disease and portal hypertension
Age: Childhood through adolescence
A substantial fraction of children develop portal hypertension, require transplantation, or die before adulthood.
Show evidence (1 reference)
PMID:36036223 SUPPORT Human Clinical
"The 10 and 18-year NLS rates were 54.4% and 40.3%."
The GALA cohort quantifies progressive loss of native-liver and event-free survival through childhood.
📊

Prevalence

2
United States
Birth Prevalence 1.0–9.0 per 100,000 1–9 per 100,000 (births)
Orphanet reports a prevalence at birth of 1-9 per 100,000 in the United States.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"1-9 / 100 000 | United States | Prevalence at birth | PMID:14684686"
The Orphanet epidemiology table provides a US birth-prevalence class for Alagille syndrome.
Europe
Birth Prevalence 0.1–0.9 per 100,000 1–9 per 1,000,000 (births)
Orphanet reports a prevalence at birth of 1-9 per 1,000,000 in Europe.
Show evidence (1 reference)
ORPHA:52 SUPPORT Other
"1-9 / 1 000 000 | Europe | Prevalence at birth | PMID:2012"
The Orphanet epidemiology table provides a European birth-prevalence class for Alagille syndrome.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Alagille syndrome:

Biliary atresia MONDO:0008867
Overlapping Features Biliary atresia is an important neonatal cholestatic differential when Alagille syndrome presents primarily with jaundice and impaired bile flow.
Progressive familial intrahepatic cholestasis MONDO:0015762
Overlapping Features PFIC overlaps through early cholestasis and pruritus but is a hepatocellular bile formation disorder rather than a multisystem Notch developmental syndrome.
📊

Related Datasets

1
RNA-seq analysis of hilar and peripheral biliary organoids from a mouse model of Alagille syndrome geo:GSE229527
To study molecular differences in wild-type and regenrated bile ducts in a mouse model of Alagille syndrome (Andersson, Chivukula, Hankeova, et al. Gastroenterology, 2018;154(4):1080-1095), we derived intrahepatic cholangiocyte organoids from hilar (pICOs) and peripheral (pICOs) regions of adult livers following a published protocol for organoids derivation and culture (Broutier et al., Nat Protoc. 2016;11:1724–1743). At passage 5, we isolated total RNA and performed bulk RNA-sequencing on 3 biological replicates from each region and genotype.
mouse BULK RNA SEQ n=12
PMID:38014627
Identified by GEO DataSets index search for Alagille syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
🔬

Clinical Trials

2
NCT02160782 PHASE_II COMPLETED
Multicenter study evaluating maralixibat for cholestatic pruritus in children with Alagille syndrome.
Target Phenotypes: Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT02160782 SUPPORT Human Clinical
"This is a long-term, open-label study with a double-blind, placebo-controlled, randomized drug withdrawal period in children with Alagille Syndrome (ALGS) designed to evaluate the safety and efficacy of LUM001 (Also known as maralixibat or MRX)."
This trial directly evaluates maralixibat for cholestatic pruritus in Alagille syndrome.
NCT04674761 PHASE_III COMPLETED
ASSERT, a double-blind randomized placebo-controlled phase 3 study of odevixibat in patients with Alagille syndrome.
Target Phenotypes: Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04674761 SUPPORT Human Clinical
"Double-blind, randomized, placebo-controlled, Phase 3 study to investigate the efficacy and safety of odevixibat compared to placebo in Patients with Alagille Syndrome."
The registry record directly identifies the completed disease-specific phase 3 odevixibat trial.
{ }

Source YAML

click to show 
name: Alagille syndrome
creation_date: '2026-04-13T04:00:00Z'
description: >-
  Alagille syndrome is an autosomal dominant multisystem developmental disorder
  caused primarily by heterozygous pathogenic variants in JAG1 and less often
  NOTCH2. The core mechanism is impaired Notch signaling during embryogenesis,
  which disrupts bile duct, cardiovascular, ocular, skeletal, renal, and facial
  development. Clinically, the syndrome is characterized by paucity of
  interlobular bile ducts with cholestasis, congenital heart disease
  particularly involving the pulmonary arteries, posterior embryotoxon,
  butterfly vertebrae, and variable extrahepatic involvement.
category: Mendelian
parents:
- hereditary disease
- cholestatic liver disease
synonyms:
- ALGS
- arteriohepatic dysplasia
- Alagille-Watson syndrome
- syndromic bile duct paucity
disease_term:
  preferred_term: Alagille syndrome
  term:
    id: MONDO:0007318
    label: Alagille syndrome
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:Q44.7
      label: Other congenital malformations of liver
    mapping_predicate: skos:narrowMatch
    mapping_source: ORPHA:52
    mapping_justification: Orphanet lists ICD-10 Q44.7 as a narrower cross-reference for Alagille syndrome.
    consistency:
    - reference: ORPHA:52
      consistent: CONSISTENT
      notes: "ICD-10:Q44.7 | Narrower"
  mondo_mappings:
  - term:
      id: MONDO:0007318
      label: Alagille syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:52
    mapping_justification: Orphanet lists MONDO:0007318 as an exact cross-reference for Alagille syndrome.
    consistency:
    - reference: ORPHA:52
      consistent: CONSISTENT
      notes: "MONDO:0007318 | Exact"
  - term:
      id: MONDO:0016862
      label: Alagille syndrome due to a JAG1 point mutation
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:0016862 is_a the MONDO:0007318 anchor of this entry and is defined as
      its JAG1 subtype (intersection_of RO:0004003 HGNC:6188). This entry curates
      JAG1 (hgnc:6188) alongside NOTCH2 (hgnc:7882), so the JAG1 child term is
      covered here. narrowMatch rather than exactMatch because the anchor also
      subsumes the NOTCH2 form and the JAG1 whole-gene deletions that this child
      term, being restricted to point mutations, excludes.
  - term:
      id: MONDO:0016861
      label: Alagille syndrome due to 20p12 microdeletion
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:0016861 is a JAG1-containing 20p12 deletion subtype of the broader
      MONDO:0007318 disease curated in this entry.
  - term:
      id: MONDO:0012439
      label: Alagille syndrome due to a NOTCH2 point mutation
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:0012439 is the NOTCH2 point-variant subtype of the broader
      MONDO:0007318 disease curated in this entry.
has_subtypes:
- name: JAG1 point-variant ALGS
  description: Alagille syndrome caused by a pathogenic JAG1 sequence variant.
  subtype_term:
    preferred_term: Alagille syndrome due to a JAG1 point mutation
    term:
      id: MONDO:0016862
      label: Alagille syndrome due to a JAG1 point mutation
  genes:
  - preferred_term: JAG1
    term:
      id: hgnc:6188
      label: JAG1
  evidence:
  - reference: PMID:9207788
    reference_title: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome.
    explanation: The original gene-discovery study directly supports a JAG1 coding-variant subtype.
- name: 20p12 deletion ALGS
  description: Alagille syndrome caused by a 20p12 deletion encompassing JAG1, sometimes with additional contiguous-gene features.
  subtype_term:
    preferred_term: Alagille syndrome due to 20p12 microdeletion
    term:
      id: MONDO:0016861
      label: Alagille syndrome due to 20p12 microdeletion
  genes:
  - preferred_term: JAG1
    term:
      id: hgnc:6188
      label: JAG1
  evidence:
  - reference: PMID:9207788
    reference_title: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome
    explanation: The original gene-discovery study directly supports the JAG1-containing deletion subtype.
- name: NOTCH2 point-variant ALGS
  description: >-
    Alagille syndrome caused by a pathogenic NOTCH2 variant; classical facies,
    posterior embryotoxon, cardiac involvement, and butterfly vertebrae occur
    less often than in JAG1-associated disease.
  subtype_term:
    preferred_term: Alagille syndrome due to a NOTCH2 point mutation
    term:
      id: MONDO:0012439
      label: Alagille syndrome due to a NOTCH2 point mutation
  genes:
  - preferred_term: NOTCH2
    term:
      id: hgnc:7882
      label: NOTCH2
  evidence:
  - reference: PMID:40742203
    reference_title: Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypic analyses revealed a significantly lower incidence of characteristic facies, posterior embryotoxon, cardiac involvement and butterfly vertebrae in individuals with NOTCH2 variants compared to those with JAG1 variants
    explanation: The GALA cohort demonstrates clinically important divergence of the NOTCH2-associated subtype.
references:
- reference: PMID:20301450
  title: Alagille Syndrome.
  tags:
  - GeneReviews
- reference: PMID:40742203
  title: Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
- reference: PMID:36036223
  title: "Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study."
- reference: PMID:34755627
  title: "Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study."
- reference: PMID:38670135
  title: "Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial."
definitions:
- name: Orphanet disease definition
  definition_type: CASE_DEFINITION
  description: >
    Orphanet defines Alagille syndrome as a rare syndrome variably characterized
    by chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral
    pulmonary artery stenosis, vertebrae segmentation anomalies, characteristic
    facies, posterior embryotoxon/anterior segment abnormalities, pigmentary
    retinopathy, and dysplastic kidneys.
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare syndrome variably characterized by chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, vertebrae segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys."
    explanation: Orphanet's definition supports the multisystem developmental framing of this entry.
external_assertions:
- name: Orphanet Alagille syndrome record
  source: Orphanet
  assertion_type: Structured disease record
  external_id: ORPHA:52
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=52
  description: >
    Orphanet structured record for Alagille syndrome, including curated
    cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA, and UMLS
    identifiers.
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0007318 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:52 to MONDO:0007318.
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:Q44.7 | Narrower"
    explanation: The Orphanet cross-reference table maps ORPHA:52 to ICD-10 Q44.7 as a narrower match.
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:118450 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:52 to OMIM 118450.
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UMLS:C0085280 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:52 to UMLS C0085280.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Alagille syndrome is classically inherited in an autosomal dominant manner,
    although penetrance and organ involvement are highly variable.
  evidence:
  - reference: PMID:30266153
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome is a complex multisystem autosomal dominant disorder with a
      wide variability in penetrance of clinical features.
    explanation: This review directly states the canonical inheritance pattern.
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for Alagille syndrome.
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Offspring of an individual with ALGS have a 50% chance of inheriting the JAG1 or NOTCH2 pathogenic variant.
    explanation: GeneReviews states the recurrence risk for autosomal dominant transmission.
prevalence:
- population: United States
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 1.0
  rate_high: 9.0
  notes: Orphanet reports a prevalence at birth of 1-9 per 100,000 in the United States.
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | United States | Prevalence at birth | PMID:14684686"
    explanation: The Orphanet epidemiology table provides a US birth-prevalence class for Alagille syndrome.
- population: Europe
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 0.1
  rate_high: 0.9
  notes: Orphanet reports a prevalence at birth of 1-9 per 1,000,000 in Europe.
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Europe | Prevalence at birth | PMID:2012"
    explanation: The Orphanet epidemiology table provides a European birth-prevalence class for Alagille syndrome.
progression:
- phase: Neonatal and infantile cholestasis
  age_range: Infancy
  notes: Liver disease often presents with cholestasis early in life, but severity is highly variable.
  evidence:
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal cholestasis occurs in 85% of cases"
    explanation: This supports early hepatic presentation in most clinically recognized cases.
- phase: Progressive liver disease and portal hypertension
  age_range: Childhood through adolescence
  notes: A substantial fraction of children develop portal hypertension, require transplantation, or die before adulthood.
  evidence:
  - reference: PMID:36036223
    reference_title: "Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 10 and 18-year NLS rates were 54.4% and 40.3%.
    explanation: The GALA cohort quantifies progressive loss of native-liver and event-free survival through childhood.
pathophysiology:
- name: JAG1 haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Loss-of-function JAG1 variants and deletions reduce functional Jagged1 dosage;
    JAG1 haploinsufficiency is the established mechanism for most Alagille syndrome.
  genes:
  - preferred_term: JAG1
    term:
      id: hgnc:6188
      label: JAG1
  biological_processes:
  - preferred_term: Notch signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0007219
      label: Notch signaling pathway
  evidence:
  - reference: PMID:40742203
    reference_title: Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      JAG1 variants cause disease through a mechanism of haploinsufficiency, but the mechanism for NOTCH2 variants is not completely understood
    explanation: The 2025 GALA analysis distinguishes established JAG1 haploinsufficiency from the unresolved NOTCH2 mechanism.
  - reference: PMID:9207788
    reference_title: "Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome.
    explanation: The landmark discovery paper directly supports JAG1 as the causal gene in Alagille syndrome.
  downstream:
  - target: Attenuated portal vascular-to-cholangiocyte Notch signaling
    description: Reduced Jagged1 dosage weakens developmental cell-cell Notch signaling around portal vessels.
  - target: Cardiovascular developmental defects
    description: Impaired Notch signaling perturbs cardiac and vascular morphogenesis.
  - target: Butterfly vertebrae
  - target: Posterior embryotoxon
  - target: Peculiar facies
  - target: Pointed chin
  - target: Frontal bossing
  - target: Protruding ear
  - target: Long nose
  - target: Vertebral segmentation defect
  - target: Spina bifida occulta
  - target: Telangiectasia of the skin
  - target: Renal hypoplasia/aplasia
  - target: Abnormal renal morphology
  - target: Intrauterine growth retardation
  - target: Cryptorchidism
  - target: Strabismus
  - target: Mild intellectual disability
  - target: Abnormality of chorioretinal pigmentation
- name: NOTCH2 pathogenic variant
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    A minority of genetically confirmed cases carry pathogenic NOTCH2 variants.
    The causal relationship is definitive, but unlike JAG1, the variant-level
    molecular mechanism is not yet completely understood.
  genes:
  - preferred_term: NOTCH2
    term:
      id: hgnc:7882
      label: NOTCH2
  biological_processes:
  - preferred_term: Notch signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0007219
      label: Notch signaling pathway
  evidence:
  - reference: PMID:40742203
    reference_title: Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease-causing variants are primarily identified in Jagged1 (JAG1), with fewer reported in NOTCH2.
    explanation: The GALA cohort confirms NOTCH2-associated Alagille syndrome while emphasizing its rarity.
  downstream:
  - target: Attenuated portal vascular-to-cholangiocyte Notch signaling
    description: Pathogenic NOTCH2 variants are expected to impair the receptor arm of the same developmental signaling axis, although their exact molecular effects vary.
- name: Attenuated portal vascular-to-cholangiocyte Notch signaling
  biological_scale: CELLULAR
  description: >-
    JAG1-expressing immature portal vascular smooth muscle cells signal to adjacent
    cholangiocyte progenitors. Loss of JAG1 at this interface attenuates Notch-dependent
    cholangiocyte differentiation and bile-duct formation.
  cell_types:
  - preferred_term: portal vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  biological_processes:
  - preferred_term: Notch signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007219
      label: Notch signaling pathway
  evidence:
  - reference: PMID:39198465
    reference_title: Generation of human iPSC-derived 3D bile duct within liver organoid by incorporating human iPSC-derived blood vessel.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Knocking out JAG1 in hiPSC-BV significantly attenuates bile duct formation, highlighting BVLO potential as a model for Alagille syndrome, a congenital biliary disease.
    explanation: Human iPSC vascularized liver organoids directly support a JAG1-dependent vascular-to-biliary developmental interface.
  downstream:
  - target: Abnormal bile duct morphogenesis
    description: Reduced portal vascular Jagged1-Notch signaling impairs cholangiocyte differentiation and duct assembly.
- name: Abnormal bile duct morphogenesis
  conforms_to: "cholestatic_liver_injury#Impaired Bile Formation and Secretion"
  biological_scale: TISSUE
  description: >-
    Developmental failure of normal intrahepatic bile duct formation produces
    paucity of interlobular bile ducts, the core hepatic lesion of Alagille
    syndrome.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  biological_processes:
  - preferred_term: intrahepatic bile duct development
    modifier: DECREASED
    term:
      id: GO:0035622
      label: intrahepatic bile duct development
  evidence:
  - reference: PMID:12420916
    reference_title: Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts
    explanation: This directly supports bile duct paucity as the defining hepatic developmental lesion.
  downstream:
  - target: Cholestatic liver disease
    description: Bile duct paucity causes impaired bile flow and chronic cholestasis.
  - target: Reduced number of intrahepatic bile ducts
  - target: Cholestasis
  - target: Hepatomegaly
- name: Cholestatic liver disease
  biological_scale: ORGANISM
  description: >-
    Bile duct paucity results in chronic cholestatic liver disease, producing
    jaundice, pruritus, fat-soluble vitamin deficiency, and progressive hepatic
    morbidity in severe cases.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:35868679
    reference_title: "Alagille Syndrome: Current Understanding of Pathogenesis, and Challenges in Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome (ALGS) is a complex heterogenous disease with a wide array of clinical manifestations in association with cholestatic liver disease.
    explanation: This review directly identifies cholestatic liver disease as a central downstream consequence.
  downstream:
  - target: Pruritus
    description: Chronic cholestasis drives severe itching and symptomatic burden.
  - target: Xanthomatosis
    description: Retention of cholesterol-rich lipids in severe cholestasis promotes cutaneous xanthomas.
  - target: Portal hypertension
    description: Progressive liver injury can culminate in clinically evident portal hypertension.
  - target: Failure to thrive
    description: Cholestatic malabsorption and fat-soluble vitamin deficiency impair growth.
  - target: Delayed puberty
    description: Chronic cholestatic malnutrition and growth impairment can delay pubertal development.
- name: Cardiovascular developmental defects
  biological_scale: TISSUE
  description: >-
    Notch pathway dysfunction disrupts embryonic cardiovascular development,
    contributing to pulmonary artery stenosis and other congenital cardiac and
    vascular abnormalities.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:30266153
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver disease is a major cause of morbidity in this population, whereas cardiac and vascular involvement accounts for most of the mortality.
    explanation: This supports a major and clinically consequential cardiovascular developmental branch in Alagille syndrome.
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notch signalling is essential for vascular morphogenesis and remodelling in mice.
    explanation: This review supports the developmental vascular role of Notch while correctly limiting the direct experimental basis to mice.
  downstream:
  - target: Peripheral pulmonary artery stenosis
  - target: Tetralogy of Fallot
  - target: Atrial septal defect
  - target: Renal artery stenosis
    description: Systemic developmental arteriopathy includes stenosis of the renal arteries.
phenotypes:
- name: Cholestasis
  category: Gastrointestinal
  diagnostic: true
  frequency: VERY_FREQUENT
  description: >-
    Chronic cholestatic liver disease is a cardinal manifestation of Alagille
    syndrome and usually reflects paucity of interlobular bile ducts.
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:12420916
    reference_title: Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts
    explanation: This directly supports cholestasis as a defining syndrome feature.
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001396 | Cholestasis | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists cholestasis as very frequent in Alagille syndrome.
- name: Peripheral pulmonary artery stenosis
  category: Cardiovascular
  diagnostic: true
  frequency: FREQUENT
  description: >-
    Peripheral pulmonary artery stenosis is one of the most characteristic
    cardiovascular manifestations of Alagille syndrome, affecting approximately
    76% of patients in large cohorts.
  phenotype_term:
    preferred_term: Peripheral pulmonary artery stenosis
    term:
      id: HP:0004969
      label: Peripheral pulmonary artery stenosis
  evidence:
  - reference: PMID:12427653
    reference_title: Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common abnormality was stenosis/hypoplasia of the branch pulmonary arteries (PAs), which was documented by imaging (n=111) or inferred from a peripheral pulmonary stenosis murmur (n=41) in 76% of subjects.
    explanation: McElhinney et al. (n=200) found branch PA stenosis in 76% of Alagille patients, firmly in the FREQUENT band.
  - reference: PMID:12420916
    reference_title: Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis
    explanation: This supports peripheral pulmonary arterial stenosis as a classic major feature.
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004969 | Peripheral pulmonary artery stenosis | Occasional (29-5%)"
    explanation: Orphanet lists this as occasional, but clinical cohort data (76% in McElhinney 2002) supports FREQUENT. The Orphanet frequency annotation appears discordant with the literature for this phenotype.
- name: Tetralogy of Fallot
  category: Cardiovascular
  frequency: OCCASIONAL
  description: >-
    Tetralogy of Fallot is present in approximately 12% of Alagille syndrome
    patients, making it the most common structural cardiac malformation after
    branch pulmonary artery stenosis.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  evidence:
  - reference: PMID:12427653
    reference_title: Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tetralogy of Fallot was present in 23 subjects and was accompanied by pulmonary atresia in 8.
    explanation: McElhinney et al. found tetralogy of Fallot in 23/200 (11.5%) Alagille patients, placing it in the OCCASIONAL frequency band.
- name: Butterfly vertebrae
  category: Skeletal
  diagnostic: true
  frequency: FREQUENT
  description: >-
    Vertebral segmentation abnormalities, especially butterfly vertebrae, are a
    classic skeletal manifestation of Alagille syndrome.
  phenotype_term:
    preferred_term: Butterfly vertebrae
    term:
      id: HP:0003316
      label: Butterfly vertebrae
  evidence:
  - reference: PMID:12420916
    reference_title: Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral arch defect
    explanation: This directly supports butterfly vertebrae as a core skeletal feature.
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Posterior embryotoxon is present in 51%, and butterfly vertebrae in 44% of patients
    explanation: The 44% estimate supports the FREQUENT band.
- name: Posterior embryotoxon
  category: Ophthalmic
  diagnostic: true
  frequency: FREQUENT
  description: >-
    Posterior embryotoxon is a characteristic ocular developmental anomaly in
    Alagille syndrome.
  phenotype_term:
    preferred_term: Posterior embryotoxon
    term:
      id: HP:0000627
      label: Posterior embryotoxon
  evidence:
  - reference: PMID:12420916
    reference_title: Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral arch defect; posterior embryotoxon
    explanation: This directly supports posterior embryotoxon as a defining ocular feature.
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Posterior embryotoxon is present in 51%, and butterfly vertebrae in 44% of patients
    explanation: The 51% estimate supports the FREQUENT band.
- name: Pruritus
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    Cholestatic pruritus is a major symptom burden in patients with hepatic
    involvement and often drives treatment escalation.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:34215014
    reference_title: "Alagille Syndrome: A Focused Review on Clinical Features, Genetics, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Medical management is supportive, focusing on clinical manifestations of disease, with liver transplant indicated for severe pruritus
    explanation: This supports severe pruritus as a clinically important hepatic symptom.
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neonatal cholestasis occurs in 85% of cases, pruritus in 74%, xanthomas in 24% of cases
    explanation: The review provides a quantitative estimate placing pruritus in the FREQUENT band.
- name: Xanthomatosis
  category: Dermatological
  frequency: OCCASIONAL
  description: Cutaneous xanthomas arise in a substantial minority of patients with severe cholestasis.
  phenotype_term:
    preferred_term: Xanthomatosis
    term:
      id: HP:0000991
      label: Xanthomatosis
  evidence:
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neonatal cholestasis occurs in 85% of cases, pruritus in 74%, xanthomas in 24% of cases
    explanation: A 24% estimate places xanthomas in the OCCASIONAL band.
- name: Portal hypertension
  category: Gastrointestinal
  frequency: FREQUENT
  description: Portal hypertension is a major later complication of progressive Alagille liver disease.
  phenotype_term:
    preferred_term: Portal hypertension
    clinical_course: PROGRESSIVE
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the cumulative incidences of portal hypertension and liver transplantation are 66% and 50% respectively at 18 years of age.
    explanation: The cumulative incidence of portal hypertension is in the FREQUENT band by age 18.
  sequelae:
  - target: Splenomegaly
- name: Abnormal renal morphology
  category: Renal
  frequency: FREQUENT
  description: Congenital renal involvement is common and includes dysplasia, hypoplasia, and other urinary-tract anomalies.
  phenotype_term:
    preferred_term: Abnormal renal morphology
    term:
      id: HP:0012210
      label: Abnormal renal morphology
  evidence:
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Kidney involvement is present in 38% of patients, and can reveal the disease.
    explanation: The reported 38% prevalence places broad renal involvement in the FREQUENT band.
- name: Renal artery stenosis
  category: Cardiovascular
  description: Renal artery stenosis is part of the systemic arteriopathy and can contribute to hypertension.
  phenotype_term:
    preferred_term: Renal artery stenosis
    term:
      id: HP:0001920
      label: Renal artery stenosis
  evidence:
  - reference: PMID:39446153
    reference_title: Kidney and vascular involvement in Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal artery stenosis and mid aortic syndrome have also frequently been reported, often associated with hypertension and stenosis and/or aneurysm of other large arteries.
    explanation: This directly supports renal artery stenosis within the Alagille vascular phenotype.
  sequelae:
  - target: Hypertension
    description: Renal arterial stenosis can produce renovascular hypertension.
    evidence:
    - reference: PMID:39446153
      reference_title: Kidney and vascular involvement in Alagille syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Renal artery stenosis and mid aortic syndrome have also frequently been reported, often associated with hypertension and stenosis and/or aneurysm of other large arteries.
      explanation: The clinical review directly associates Alagille renal-artery stenosis with hypertension.
- name: Splenomegaly
  category: Gastrointestinal
  description: Splenomegaly may occur, including as a clinical manifestation of portal hypertension.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal abnormalities, growth failure, behavioral differences, splenomegaly, retinal changes, and vascular abnormalities may also occur.
    explanation: GeneReviews includes splenomegaly among recognized manifestations.
- name: Abnormality of chorioretinal pigmentation
  category: Ophthalmic
  description: Retinal pigmentary changes are part of the broader ocular phenotype beyond posterior embryotoxon.
  phenotype_term:
    preferred_term: Abnormality of chorioretinal pigmentation
    term:
      id: HP:0007661
      label: Abnormality of chorioretinal pigmentation
  evidence:
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal abnormalities, growth failure, behavioral differences, splenomegaly, retinal changes, and vascular abnormalities may also occur.
    explanation: GeneReviews supports retinal changes as a recognized extrahepatic manifestation.
- name: Peculiar facies
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Characteristic facies are a classic craniofacial component of Alagille
    syndrome, including coarse facial features, pointed chin, round face,
    frontal bossing, and long nose.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:12420916
    reference_title: Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral arch defect; posterior embryotoxon and peculiar facies.
    explanation: This directly supports characteristic facies as a classic feature of Alagille syndrome.
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000280 | Coarse facial features | Frequent (79-30%)"
    explanation: The FREQUENT band is carried over from Orphanet's coarse-facial-features row as a quantified component of the broader characteristic facies.
- name: Failure to thrive
  category: Growth
  frequency: VERY_FREQUENT
  description: >-
    Failure to thrive is very frequent in Alagille syndrome, reflecting
    cholestatic malabsorption and fat-soluble vitamin deficiency.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001508 | Failure to thrive | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists failure to thrive as very frequent in Alagille syndrome.
- name: Hepatomegaly
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Hepatomegaly is very frequent in Alagille syndrome, reflecting chronic
    cholestatic liver disease.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002240 | Hepatomegaly | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists hepatomegaly as very frequent in Alagille syndrome.
- name: Reduced number of intrahepatic bile ducts
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Paucity of intrahepatic bile ducts is the histopathological hallmark of
    Alagille syndrome.
  phenotype_term:
    preferred_term: Reduced number of intrahepatic bile ducts
    term:
      id: HP:0006571
      label: Reduced number of intrahepatic bile ducts
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006571 | Reduced number of intrahepatic bile ducts | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists reduced intrahepatic bile ducts as very frequent.
  - reference: PMID:12420916
    reference_title: Alagille syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      chronic cholestasis owing to paucity of interlobular bile ducts
    explanation: This directly supports bile duct paucity as a defining feature.
- name: Pointed chin
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Pointed chin is a frequent facial feature contributing to the characteristic
    triangular facies of Alagille syndrome.
  phenotype_term:
    preferred_term: Pointed chin
    term:
      id: HP:0000307
      label: Pointed chin
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000307 | Pointed chin | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists pointed chin as frequent in Alagille syndrome.
- name: Frontal bossing
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Frontal bossing is a frequent craniofacial feature of Alagille syndrome,
    contributing to the characteristic prominent forehead.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002007 | Frontal bossing | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists frontal bossing as frequent in Alagille syndrome.
- name: Protruding ear
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Protruding ears are a frequent feature of the characteristic facies in
    Alagille syndrome.
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000411 | Protruding ear | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists protruding ear as frequent in Alagille syndrome.
- name: Long nose
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Long nose is a frequent facial feature contributing to the characteristic
    facies of Alagille syndrome.
  phenotype_term:
    preferred_term: Long nose
    term:
      id: HP:0003189
      label: Long nose
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003189 | Long nose | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists long nose as frequent in Alagille syndrome.
- name: Vertebral segmentation defect
  category: Skeletal
  frequency: FREQUENT
  description: >-
    Vertebral segmentation defects beyond butterfly vertebrae are frequent
    skeletal manifestations of Alagille syndrome.
  phenotype_term:
    preferred_term: Vertebral segmentation defect
    term:
      id: HP:0003422
      label: Vertebral segmentation defect
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003422 | Vertebral segmentation defect | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists vertebral segmentation defects as frequent.
- name: Spina bifida occulta
  category: Skeletal
  frequency: FREQUENT
  description: >-
    Spina bifida occulta is a frequent vertebral anomaly in Alagille syndrome.
  phenotype_term:
    preferred_term: Spina bifida occulta
    term:
      id: HP:0003298
      label: Spina bifida occulta
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003298 | Spina bifida occulta | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists spina bifida occulta as frequent in Alagille syndrome.
- name: Intrauterine growth retardation
  category: Growth
  frequency: FREQUENT
  description: >-
    Intrauterine growth retardation is frequent, reflecting prenatal impact of
    the developmental disorder.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001511 | Intrauterine growth retardation | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists IUGR as frequent in Alagille syndrome.
- name: Telangiectasia of the skin
  category: Dermatological
  frequency: FREQUENT
  description: >-
    Cutaneous telangiectasia is a frequent dermatological manifestation of
    Alagille syndrome.
  phenotype_term:
    preferred_term: Telangiectasia of the skin
    term:
      id: HP:0100585
      label: Telangiectasia of the skin
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100585 | Telangiectasia of the skin | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists skin telangiectasia as frequent in Alagille syndrome.
- name: Hypertension
  category: Cardiovascular
  frequency: OCCASIONAL
  description: >-
    Hypertension occurs occasionally in Alagille syndrome, potentially related
    to renal involvement.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000822 | Hypertension | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists hypertension as occasional in Alagille syndrome.
- name: Atrial septal defect
  category: Cardiovascular
  frequency: OCCASIONAL
  description: >-
    Atrial septal defects occur occasionally as part of the congenital heart
    disease spectrum in Alagille syndrome.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001631 | Atrial septal defect | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists atrial septal defect as occasional in Alagille syndrome.
- name: Renal hypoplasia/aplasia
  category: Renal
  frequency: OCCASIONAL
  description: >-
    Renal hypoplasia or aplasia reflects the developmental renal involvement in
    Alagille syndrome.
  phenotype_term:
    preferred_term: Renal hypoplasia/aplasia
    term:
      id: HP:0008678
      label: Renal hypoplasia/aplasia
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008678 | Renal hypoplasia/aplasia | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists renal hypoplasia/aplasia as occasional.
- name: Delayed puberty
  category: Endocrine
  frequency: OCCASIONAL
  description: >-
    Delayed puberty occurs occasionally, likely related to chronic cholestatic
    malnutrition and growth impairment.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000823 | Delayed puberty | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists delayed puberty as occasional in Alagille syndrome.
- name: Cryptorchidism
  category: Genitourinary
  frequency: OCCASIONAL
  description: >-
    Cryptorchidism occurs occasionally in male patients with Alagille syndrome.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000028 | Cryptorchidism | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists cryptorchidism as occasional in Alagille syndrome.
- name: Strabismus
  category: Ophthalmic
  frequency: OCCASIONAL
  description: >-
    Strabismus occurs occasionally as part of the ocular involvement in
    Alagille syndrome.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000486 | Strabismus | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists strabismus as occasional in Alagille syndrome.
- name: Mild intellectual disability
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Mild intellectual disability occurs occasionally in Alagille syndrome.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: ORPHA:52
    reference_title: "Alagille syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001256 | Intellectual disability, mild | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists mild intellectual disability as occasional.
histopathology:
- name: Paucity of interlobular bile ducts
  diagnostic: true
  description: >-
    Reduced interlobular bile ducts on liver biopsy are the characteristic hepatic
    histopathologic lesion, although a molecular diagnosis may establish Alagille syndrome without biopsy.
  finding_term:
    preferred_term: paucity of interlobular bile ducts
  evidence:
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis
    explanation: GeneReviews directly identifies bile duct paucity as the characteristic biopsy finding.
biochemical:
- name: Elevated serum bile acids
  presence: INCREASED
  context: Cholestasis commonly produces high serum bile-acid concentrations and the level is a pharmacodynamic treatment readout.
  biomarker_term:
    preferred_term: serum bile acids
  evidence:
  - reference: PMID:38670135
    reference_title: "Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cholestasis-associated clinical features can include high serum bile acids and severe pruritus
    explanation: The ASSERT trial identifies high serum bile acids as a disease-associated biochemical feature.
- name: Total bilirubin in infancy
  presence: INCREASED
  context: Total bilirubin between six and twelve months is a prognostic biomarker for portal hypertension and native-liver survival.
  biomarker_term:
    preferred_term: total serum bilirubin
  evidence:
  - reference: PMID:36036223
    reference_title: "Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes.
    explanation: The international GALA cohort supports infant total bilirubin as an objective prognostic biomarker.
  reference_ranges:
  - unit: mg/dL
    population: children with Alagille syndrome, age 6-12 months
    notes: Prognostic bands for later clinically evident portal hypertension and liver transplantation; these are not general laboratory reference intervals.
    evidence:
    - reference: PMID:36036223
      reference_title: "Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl.
      explanation: GALA provides directly computable infant total-bilirubin prognostic tiers.
    interpretation_bands:
    - name: Lower hepatic-risk band
      upper_bound: 5.0
      unit: mg/dL
      interpretation: Median total bilirubin below 5.0 mg/dL was the reference group and was associated with better hepatic outcomes.
    - name: Intermediate hepatic-risk band
      lower_bound: 5.0
      upper_bound: 10.0
      unit: mg/dL
      interpretation: Median total bilirubin from 5.0 to below 10.0 mg/dL was associated with a 4.8-fold increased transplantation risk relative to below 5.0 mg/dL.
    - name: High hepatic-risk band
      lower_bound: 10.0
      unit: mg/dL
      interpretation: Median total bilirubin above 10.0 mg/dL was associated with a 15.6-fold increased transplantation risk relative to below 5.0 mg/dL.
genetic:
- name: JAG1
  gene_term:
    preferred_term: JAG1
    term:
      id: hgnc:6188
      label: JAG1
  association: Causal haploinsufficiency or pathogenic heterozygous variant
  frequency: VERY_FREQUENT
  case_fractions:
  - population: GALA international cohort
    case_fraction_percent: 94.7
    cohort_size: 952
    notes: 902 of 952 individuals carried JAG1 variants.
    evidence:
    - reference: PMID:40742203
      reference_title: Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants.
      explanation: The contemporary GALA cohort quantifies the JAG1-associated share of cases.
  evidence:
  - reference: PMID:40742203
    reference_title: Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants.
    explanation: This large molecularly defined cohort directly supports JAG1 as the predominant causal gene.
- name: NOTCH2
  gene_term:
    preferred_term: NOTCH2
    term:
      id: hgnc:7882
      label: NOTCH2
  association: Causal heterozygous variant
  frequency: VERY_RARE
  case_fractions:
  - population: GALA international cohort
    case_fraction_percent: 3.6
    cohort_size: 952
    notes: 34 of 952 individuals carried NOTCH2 variants.
    evidence:
    - reference: PMID:40742203
      reference_title: Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants.
      explanation: The contemporary GALA cohort quantifies the NOTCH2-associated share of cases.
  evidence:
  - reference: PMID:40742203
    reference_title: Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants.
    explanation: This molecularly defined cohort directly supports NOTCH2 as a rare causal gene.
  - reference: CGGV:assertion_044f1413-e1cd-4212-9e9a-a4d9c66c08dc-2025-02-26T170000.000Z
    reference_title: "NOTCH2 / Alagille syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NOTCH2 | HGNC:7882 | Alagille syndrome | MONDO:0007318 | AD | Definitive"
    explanation: ClinGen classifies the NOTCH2-Alagille syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Maralixibat
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: maralixibat
      term:
        id: NCIT:C170148
        label: Maralixibat
  description: >-
    Ileal bile acid transporter inhibition with maralixibat is used to reduce
    cholestatic pruritus in Alagille syndrome.
  target_phenotypes:
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  - preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:34755627
    reference_title: "Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect.
    explanation: The disease-specific randomized withdrawal period directly supports durable reductions in serum bile acids and pruritus.
- name: Odevixibat
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: odevixibat
      term:
        id: NCIT:C166598
        label: Odevixibat
  description: >-
    Ileal bile acid transporter inhibition with odevixibat reduces serum bile
    acids and cholestatic pruritus in Alagille syndrome.
  target_phenotypes:
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  - preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:38670135
    reference_title: "Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome.
    explanation: The phase 3 ASSERT trial directly supports odevixibat for pruritus and serum bile-acid reduction.
- name: JAG1-upregulating antisense oligonucleotide (preclinical)
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    target_gene:
      preferred_term: JAG1
      term:
        id: hgnc:6188
        label: JAG1
    target_transcript: JAG1 mRNA upstream open reading frame
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  description: >-
    Experimental ASOs targeting a JAG1 mRNA upstream open reading frame increase
    JAG1 translation; efficacy has so far been demonstrated only in cells and a
    Jag1-haploinsufficient mouse model. The abstract reports multiple translational
    mechanisms without identifying the optimized ASO's specific mechanism, so an
    oligonucleotide_mechanism enum is not asserted.
  target_mechanisms:
  - target: JAG1 haploinsufficiency
    treatment_effect: ACTIVATES
    description: The ASO is designed to increase translation from the remaining functional JAG1 allele.
    evidence:
    - reference: PMID:40980686
      reference_title: Antisense oligonucleotide-mediated upregulation of Jag1 ameliorates liver disease phenotypes in a mouse model of Alagille syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        certain ASOs targeting the upstream open reading frame (uORF) increased JAG1 protein levels
      explanation: The experiment directly supports activation of residual JAG1 translation as the treatment mechanism.
  evidence:
  - reference: PMID:40980686
    reference_title: Antisense oligonucleotide-mediated upregulation of Jag1 ameliorates liver disease phenotypes in a mouse model of Alagille syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that certain ASOs targeting the upstream open reading frame (uORF) increased JAG1 protein levels in various cell lines and ALGS patient-derived cells.
    explanation: Cell experiments support the intended translational-upregulation mechanism.
  - reference: PMID:40980686
    reference_title: Antisense oligonucleotide-mediated upregulation of Jag1 ameliorates liver disease phenotypes in a mouse model of Alagille syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      When newborn Jag1 +/- mice were treated with ASO, improved bile duct development was observed, along with trends of reduced plasma bile acids, bilirubin, and triglyceride levels, implying improved liver function.
    explanation: Mouse treatment data provide preclinical evidence while not asserting human efficacy.
- name: Liver transplantation
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: liver transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  description: >-
    Liver transplantation is used for severe hepatic disease, growth failure,
    portal hypertension, or refractory pruritus.
  target_phenotypes:
  - preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:34215014
    reference_title: "Alagille Syndrome: A Focused Review on Clinical Features, Genetics, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      liver transplant indicated for severe pruritus, liver synthetic dysfunction, portal hypertension, bone fractures, and/or growth failure.
    explanation: This directly supports liver transplantation for severe hepatic manifestations.
- name: Nutritional and fat-soluble vitamin support
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  description: >-
    Calorie optimization and replacement of fat-soluble vitamins address growth
    failure and malabsorption associated with chronic cholestasis.
  target_phenotypes:
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      optimized nutrition and replacement of fat-soluble vitamins as needed
    explanation: GeneReviews recommends nutritional optimization and vitamin replacement as supportive management.
- name: Activity and alcohol risk counseling
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Behavioral Counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  description: Counsel patients to avoid contact sports and, when liver disease is present, alcohol consumption.
  evidence:
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Agents/circumstances to avoid: Contact sports; alcohol consumption if liver disease is present.
    explanation: GeneReviews explicitly lists these risk-reduction recommendations.
diagnosis:
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    Diagnostic confirmation is achieved by identifying a pathogenic JAG1 or
    NOTCH2 variant.
  results: Heterozygous pathogenic variant in JAG1 or NOTCH2 supports the diagnosis.
  evidence:
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of ALGS is established in a proband who meets clinical diagnostic criteria and/or has a heterozygous pathogenic variant in JAG1 or NOTCH2 identified by molecular genetic testing.
    explanation: GeneReviews directly supports clinical criteria and JAG1/NOTCH2 molecular testing as diagnostic routes.
- name: Liver biopsy
  diagnosis_term:
    preferred_term: biopsy of liver
    term:
      id: NCIT:C51677
      label: Liver Biopsy
  description: >-
    Liver biopsy can document paucity of interlobular bile ducts in patients
    with hepatic-predominant presentations.
  results: Paucity of interlobular bile ducts supports the hepatic diagnosis.
  evidence:
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis
    explanation: GeneReviews directly links liver biopsy with the diagnostic finding of bile duct paucity.
- name: Hepatocellular carcinoma surveillance
  diagnosis_term:
    preferred_term: liver ultrasound surveillance
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  description: Serum alpha-fetoprotein and liver ultrasound are used every six months for hepatocellular carcinoma surveillance.
  results: A new focal liver lesion or rising alpha-fetoprotein requires diagnostic evaluation.
  evidence:
  - reference: PMID:20301450
    reference_title: Alagille Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      serum alpha-fetoprotein and liver ultrasound every six months
    explanation: GeneReviews gives the disease-specific hepatocellular carcinoma surveillance interval and modalities.
differential_diagnoses:
- name: Biliary atresia
  disease_term:
    preferred_term: biliary atresia
    term:
      id: MONDO:0008867
      label: biliary atresia
  description: >-
    Biliary atresia is an important neonatal cholestatic differential when
    Alagille syndrome presents primarily with jaundice and impaired bile flow.
- name: Progressive familial intrahepatic cholestasis
  disease_term:
    preferred_term: progressive familial intrahepatic cholestasis
    term:
      id: MONDO:0015762
      label: progressive familial intrahepatic cholestasis
  description: >-
    PFIC overlaps through early cholestasis and pruritus but is a hepatocellular
    bile formation disorder rather than a multisystem Notch developmental syndrome.
clinical_trials:
- name: NCT02160782
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Multicenter study evaluating maralixibat for cholestatic pruritus in
    children with Alagille syndrome.
  target_phenotypes:
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: clinicaltrials:NCT02160782
    reference_title: Long-Term, Open-Label Study With a Double-Blind, Placebo-Controlled, Randomized Drug Withdrawal Period of LUM001 (Maralixibat), an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Patients With Alagille Syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a long-term, open-label study with a double-blind, placebo-controlled, randomized drug withdrawal period in children with Alagille Syndrome (ALGS) designed to evaluate the safety and efficacy of LUM001 (Also known as maralixibat or MRX).
    explanation: This trial directly evaluates maralixibat for cholestatic pruritus in Alagille syndrome.
- name: NCT04674761
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ASSERT, a double-blind randomized placebo-controlled phase 3 study of
    odevixibat in patients with Alagille syndrome.
  target_phenotypes:
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: clinicaltrials:NCT04674761
    reference_title: A Phase 3 Double-blind, Randomized, Placebo-controlled Study of the Safety and Efficacy of Odevixibat (A4250) in Patients With Alagille Syndrome (ASSERT)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Double-blind, randomized, placebo-controlled, Phase 3 study to investigate the efficacy and safety of odevixibat compared to placebo in Patients with Alagille Syndrome.
    explanation: The registry record directly identifies the completed disease-specific phase 3 odevixibat trial.
datasets:
- accession: geo:GSE229527
  title: RNA-seq analysis of hilar and peripheral biliary organoids from a mouse model of Alagille syndrome
  description: To study molecular differences in wild-type and regenrated bile ducts in a mouse model of Alagille syndrome (Andersson, Chivukula, Hankeova, et al. Gastroenterology, 2018;154(4):1080-1095), we derived intrahepatic cholangiocyte organoids from hilar (pICOs) and peripheral (pICOs) regions of adult livers following a published protocol for organoids derivation and culture (Broutier et al., Nat Protoc. 2016;11:1724–1743). At passage 5, we isolated total RNA and performed bulk RNA-sequencing on 3 biological replicates from each region and genotype.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 12
  publication: PMID:38014627
  notes: Identified by GEO DataSets index search for Alagille syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
📚

References & Deep Research

References

5
PMID:20301450
Alagille Syndrome.
No top-level findings curated for this source.
PMID:40742203
Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines.
No top-level findings curated for this source.
PMID:36036223
Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.
No top-level findings curated for this source.
PMID:34755627
Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study.
No top-level findings curated for this source.
PMID:38670135
Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Publication readiness review: Alagille syndrome · 2026-08-05T02:41:37Z · View source

Completed a claim-level publication review against GeneReviews, disease-specific GALA natural-history cohorts, randomized maralixibat and odevixibat trials, and recent mechanistic literature. Separated JAG1 and NOTCH2 disease mechanisms and subtypes; added quantitative natural history, renal and ocular manifestations, histopathology, biochemical biomarkers, surveillance, supportive care, an approved drug, a phase III trial, and a preclinical JAG1-upregulating strategy; removed unsupported or misleading phenotype claims; and corrected ontology, evidence polarity, source type, snippet, scope, and pathograph issues. Cross-checked the repository deep-research artifact and performed a current primary-literature search. Deliberately omitted the Orphanet corneal-dystrophy row because disease-specific sources support anterior-segment findings rather than corneal dystrophy, and removed the ventricular-septal-defect frequency that had been inferred from tetralogy-of-Fallot evidence; neither claim should be restored from those sources without direct support.

Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Alagille syndrome. Core disease mechanisms, molecular and cellular pathway...
Asta Scientific Corpus Retrieval 20 citations 2026-04-13T13:49:48.169945

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Alagille syndrome. Core disease mechanisms, molecular and cellular pathway...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Ocular Findings in Siblings With Alagille Syndrome: A Report of Two Cases

  • Authors: Ricardo A Murati Calderón, Julian A Menendez Sepulveda, N. Izquierdo
  • Year: 2025
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/ab7b77221dbad9c4fc3b0f034fe9d63b00dd547a
  • DOI: 10.7759/cureus.95312
  • PMID: 41293383
  • PMCID: 12641326
  • Summary: Two Latino siblings with ALGS and glaucoma share the previously described JAG1 c.925G>C (p.Gly309Arg) variant, suggesting that disruption of the Notch pathway may increase the risk of anterior-segment (mesodermal) dysgenesis and predispose individuals with ALGS to glaucoma.
  • Evidence snippets:
  • Snippet 1 (score: 0.466) > Alagille syndrome (ALGS) is a rare multisystemic disorder characterized by a wide range of clinical manifestations, including ophthalmic findings [1]. Major diagnostic criteria of patients with ALGS include cholestatic liver disease due to bile duct paucity, characteristic facial dysmorphism, cardiovascular anomalies (mainly pulmonary artery stenosis), and renal and skeletal abnormalities, such as butterfly vertebrae [2]. Ocular features in patients with the syndrome include posterior embryotoxon, iris abnormalities, optic disc anomalies, diffuse fundus hypopigmentation, and speckling of the retinal pigment epithelium [1,3]. > The primary genetic cause of ALGS is mutations in the JAG1 gene, inherited as an autosomal dominant trait [4]. The JAG1 gene encodes the jagged 1 protein, a key component of the Notch signaling pathway. Human jagged 1 is the ligand for the receptor notch 1, which is involved in signaling processes [5]. JAG1-Notch signaling regulates the differentiation of endothelial cells into mesenchymal cells, a process known as endothelial-mesenchymal transition [6]. This pathway is vital for forming bile ducts, heart valves, and other key structures, such as the neural-crest-derived anterior segment of the eye, commonly affected in ALGS [7,8]. > Perturbation of the Notch pathway in the anterior segment has been implicated in the prominence of Schwalbe's line, known as posterior embryotoxon, abnormal development of the trabecular meshwork and Schlemm's canal, and various iris anomalies [1]. These alterations provide a biologically plausible mechanism for impaired aqueous outflow and subsequent elevation of intraocular pressure (IOP). In animal models, mutations in JAG1 have been shown to similarly cause abnormalities and dysgenesis of the trabecular meshwork and iridocorneal angle, supporting this mechanistic link [9]. > Alagille syndrome affects approximately 1 in 30,000 to 70,000 live births globally and exhibits variable expressivity, complicating diagnosis and management [1].

[2] Successful long-term survival following lipiodol chemoembolization for hepatocellular carcinoma in Alagille syndrome: A case report

  • Authors: Imad Akasbi, I. Chaouche, N. Bouardi, A. Akammar, H. O. Chahdi et al.
  • Year: 2025
  • Venue: Radiology Case Reports
  • URL: https://www.semanticscholar.org/paper/6679c324bcffe0ca254e661188deda9454e73e67
  • DOI: 10.1016/j.radcr.2025.04.125
  • PMID: 40492163
  • PMCID: 12148378
  • Summary: A 29-year-old female, diagnosed with Alagille syndrome in infancy, who developed infiltrative HCC at age 20 and underwent lipiodol-based transarterial chemoembolization (TACE) in 2015, has achieved an exceptional 9-year survival post-treatment with stable imaging and no recurrence, highlighting TACE’s potential as an effective palliative treatment for HCC in Alagille syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.456) > The development of HCC in Alagille syndrome is caused by fibrotic changes, genetic instability in hepatocytes and oncogenic mutations [1][2][3]. Furthermore, in the context of genetic predisposition, mutations in the JAG1 or NOTCH2 genes can contribute directly to carcinogenesis by perturbing cell signaling pathways [3][4][5][6]. Nonspecific markers such as bilirubin and the presence of xanthomas have been identified as potential predictors of severe liver damage with an increased risk of malignancy [ 1 ,2 ,4 ,5 ]. > The management of Alagille syndrome and its complications requires a multidisciplinary approach. Regular monitoring of liver function and imaging is essential for early detection of malignancies. Liver transplantation remains the definitive treatment for end-stage liver disease and HCC in this syndrome, offering better survival outcomes. However, challenges such as organ availability and per-operative risks need to be surmounted [3][4][5]. > HCC in Alagille syndrome remains poorly studied, with only a handful of reported cases. In a retrospective study by Pham et al., 1 patient with Alagille syndrome underwent chemoembolization with good response, though liver transplantation was ultimately required. Geramizadeh et al. described another case of pediatric HCC in Alagille syndrome, where chemoembolization was performed twice, achieving a durable clinical and radiological response [ 7-9 ] Our patient's case stands out due to the exceptional long-term survival of 9 years without liver transplantation, highlighting the potential role of repeated chemoembolization as a bridging or palliative strategy when transplant is not feasible. > Emerging therapies for Alagille syndrome target the underlying genetic and molecular mechanisms, especially the Notch signaling pathway (Kohut et al. [ 3 ]). Gene-based treatments and small molecules are being developed to address JAG1 or NOTCH2 mutations. Novel agents also aim to improve bile acid metabolism and reduce fibrosis (Ayoub et al. [ 5 ]). These approaches may help manage cholestasis and prevent liver damage.

[3] Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

  • Authors: Ana Sánchez-Monteagudo, E. Ripollés, M. Berenguer, C. Espinós
  • Year: 2021
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/e55ab21bb219d044caf3ddbc8064ed4e79fafe0d
  • DOI: 10.3390/biomedicines9091100
  • PMID: 34572285
  • PMCID: 8471362
  • Citations: 37
  • Influential citations: 1
  • Summary: The characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.449) > Alagille syndrome (ALGS; MIM 118450) is a multisystem disorder caused by mutations in JAG1 or NOTCH2 genes transmitted in an autosomal dominant way. ALGS is characterized by the scarcity of bile ducts in liver biopsy and, at least, the presence of three of five clinical features: cholestasis, congenital heart defects, ocular abnormalities, bone anomalies and characteristic facies. Renal disease, development, and growth retardation may occur less frequently. > Nearly 400 mutations have been annotated for JAG1 implicated in ALGS, while cases owing to NOTCH2 mutations are less frequent. JAG1 encodes Jagged-1 protein, a ligand of the Notch-1 family of transmembrane receptors, which are involved in signaling pathways related to cell fate determination during embryogenesis. Overall, there are no clear genotype-phenotype correlations for this syndrome and its high variable expressivity and incomplete penetrance are well recognized [135,136]. Amson et al. [137] reported two siblings who both presented with liver disease but were carriers of two different genetic alterations. The index case was diagnosed with ALGS, and molecular analysis showed that he was a carrier of a de novo duplication in JAG1 and a mutation in ATP7B. His brother was diagnosed with WD and resulted to be a compound heterozygous for ATP7B mutations. The index case had abnormal liver function, but he had no bile duct paucity on liver biopsy. So far, the question whether the ATP7B variant contributes to the clinical outcome in the index case remains unanswered.

[4] Phenotypic Divergence of JAG1‐ and NOTCH2‐Associated Alagille Syndrome & Disease‐Specific NOTCH2 Variant Classification Guidelines

  • Authors: Shannon M. Vandriel, Li-Ting Li, H. She, Jian-She Wang, K. Loomes et al.
  • Year: 2025
  • Venue: Liver International
  • URL: https://www.semanticscholar.org/paper/9afc79d27f6315be4479512b7893a3ee7c5deb70
  • DOI: 10.1111/liv.70251
  • PMID: 40742203
  • PMCID: 12312628
  • Citations: 1
  • Summary: Using a large, international patient cohort acquired through the Global ALagille Alliance (GALA) study, this work sought to improve classification of NOTCH2 variants and study phenotypic differences between NOTCH2‐ and JAG1‐related disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.443) > Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder that is the most common inherited cause of neonatal cholestasis, with an overall incidence of 1:30 000 [1]. Additional clinical features include characteristic facies, cardiac, skeletal, renal, vascular and ocular involvement [2][3][4][5][6]. The molecular aetiology of ALGS stems from dysfunctional Notch signalling caused by pathogenic variants in either the Notch pathway ligand Jagged1 (JAG1) or the Notch receptor, NOTCH2, which account for 94.3% and 2.5% of cases, respectively [7]. A clinical diagnosis of ALGS relies on the presence of at least three disease features or the presence of one disease feature and either a family history in a first degree relative or a confirmed pathogenic/likely pathogenic variant identified in JAG1 or NOTCH2. JAG1-related ALGS has been well-characterised with over 700 variants described in the Human Gene Mutation Database (HGMD) [8]. The majority of JAG1 variants (including full gene deletions) result in loss-of-function (LoF) of the JAG1 protein, implicating haploinsufficiency as the underlying disease mechanism [4,9]. In ALGS, there is remarkable variability in both disease severity and organ involvement including among family members harbouring the same pathogenic variant [3,[10][11][12][13][14]. The mechanisms underlying variable expressivity remain unknown but likely involve the contribution of genetic modifiers [15][16][17][18]. Consequently, cohort-based studies have failed to establish a genotype-phenotype association among patients with ALGS [19][20][21]. > The functional consequences of variants in NOTCH2 are less well understood, with only 35 variants reported in HGMD [8]. Given the paucity of supportive functional data and the low number of individuals with a NOTCH2 variant, variant of uncertain significance (VOUS) rates for NOTCH2 are high.

[5] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[6] Generation of iPSC line NCHi012-A from a patient with Alagille syndrome and heterozygous pathogenic variant in the JAG1 gene

  • Authors: D. Cunningham, Isaac Stanberry, Shiqiao Ye, Matthew Alonzo, Ming-Tao Zhao et al.
  • Year: 2023
  • Venue: Stem cell research
  • URL: https://www.semanticscholar.org/paper/878fcbd80b2dee6304fe62f6e00c3eca45811630
  • DOI: 10.1016/j.scr.2023.103177
  • PMID: 37549562
  • PMCID: 10528323
  • Citations: 1
  • Summary: An initial characterization of NCHi012-A is reported, derived from an ALGS patient with cholestatic liver disease and mild pulmonary stenosis, who is heterozygous for a 2 bp deletion in the JAG1 coding sequence.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > Alagille syndrome (ALGS) is an autosomal dominant genetic disorder with incomplete penetrance that affects ~1 in 70,000 live births (Kohut et al., 2021). Clinical features of ALGS are variable, but primarily involve a paucity of intrahepatic bile ducts resulting in cholestasis, and may also include cardiac, skeletal, ocular and renal abnormalities. The most common cardiac defects are peripheral pulmonary stenosis (75%) and tetralogy of Fallot (7-13%) (Mitchell et al., 2018). About 95% of ALGS patients carry pathogenic variants in JAG1 that encodes Jagged1, a transmembrane ligand that binds Notch receptors to mediate inter-cellular signaling (Gilbert et al., 2019). In ALGS, JAG1 variants are present across all regions of the gene, with no clear correlation between mutation position and specific clinical features (Kohut et al., 2021). Thus, it is thought that the dominant inheritance of ALGS likely arises from JAG1 haploinsufficiency rather than dominant negative effects. > Differences in genetic modifiers between ALGS patients may account for the broad range of phenotypes they display. Differentiation of patient-derived iPSC lines into relevant cell lineages in vitro provides a powerful approach toward identifying the factors and mechanisms that contribute to the complex ALGS phenotype. > Here we describe iPSC line NCHi012-A that was derived from an ALGS patient with end-stage cholestatic liver disease requiring a liver transplant, chronic kidney disease (Stage I) with secondary hypertension and mild bilateral pulmonary stenosis. NCHi012-A is heterozygous for a 2 bp deletion [NM_000214.3(JAG1): c.1485_1486delCT] that results in a frameshift near the middle of the JAG1 coding sequence (dbSNP: rs876660981) (Raas-Rothschild et al., 2002).

[7] Advances in origin, evolution, and pathogenesis of optic disc drusen: A narrative review

  • Authors: Xiyuan Liu, Yan Yan
  • Year: 2025
  • Venue: Indian Journal of Ophthalmology
  • URL: https://www.semanticscholar.org/paper/c6c18910b365394e37939bef28b5ffd85d27d7b1
  • DOI: 10.4103/IJO.IJO_937_24
  • PMID: 40272291
  • PMCID: 12121874
  • Citations: 4
  • Influential citations: 1
  • Summary: A database search on PubMed and Google Scholar for ODD publications used the terms: (“optic disc drusen”) OR (“optic nerve head drusen”) OR (“drusen of optic nerve head”) to identify publications.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > Volume 73 Issue 5 one out of 27 relatives had buried ODD, estimated at 3.7%, higher than the average prevalence estimates in the studies. > Accordingly, researchers have attempted to find candidate genes for ODD [Table 1]. In 1997, Nischal reported a strong correlation between Alagille syndrome (AS) and ODD in young children under ultrasound evidence. [13] The findings showed that the prevalence of unilateral ODD and bilateral ODD in patients with AS was 90% and 65%, respectively. ODD was the most common ophthalmologic abnormality in infants with several types of cholestasis, including AS, with an incidence of 10.7%. [14] Gilbert attributed the causal genes for AS to JAGGED1 within 20p12 and NOTCH2 within 1p12 by disrupting the Notch signaling pathway. [15] Given the critical role of Notch signaling in cellular fate determination and its activity during development and in organ systems, it is hypothesized that ODD may be independently influenced by JAGGED1 and NOTCH2 genes. ODD has recently been identified as a complex ophthalmic syndrome linked to a mutation in the membrane-type frizzled-related protein (MFRP) gene. Studies suggested that MFRP might be involved with Table 1: Lists of possible genes and syndromes associated with optic disc drusen and related clinical presentations

[8] Alagille Syndrome and Its Clinical and Laboratory Features: A Case Report

  • Authors: L. Abenavoli, Luigi Boccuto, A. Corea, M. Gambardella, R. Spagnuolo et al.
  • Year: 2022
  • Venue: Livers
  • URL: https://www.semanticscholar.org/paper/adcaf541c36f734e74a2cf2557c42c38606c1277
  • DOI: 10.3390/livers2040021
  • Summary: A case of an individual with ALGS presenting with congenital chronic cholestasis and a long clinical history, in which pruritus is the main symptom is described.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > Alagille Syndrome and Its Clinical and Laboratory Features: A Case Report

[9] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

  • Authors: K. Lourida, G. Louridas
  • Year: 2022
  • Venue: Cardiogenetics
  • URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
  • DOI: 10.3390/cardiogenetics12020015
  • Citations: 4
  • Influential citations: 1
  • Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[10] Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome

  • Authors: E. Micaglio, A. Andronache, P. Carrera, M. Monasky, E. Locati et al.
  • Year: 2019
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/32a91436094e3785545efb46d990e7a5b3173304
  • DOI: 10.3390/ijms20246247
  • PMID: 31835735
  • PMCID: 6940840
  • Citations: 16
  • Summary: A novel pathogenic heterozygous JAG1 mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagilles patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > It has been known since 2000 that the JAG1 gene is expressed in normal human neural tube [12]. In spite of this, clinical descriptions of neural tube defects in molecularly confirmed Alagille patients are limited. No functional data about the role of the JAG1 heterozygous mutation in neural tube defects are available to date. However, it has been demonstrated that apical/basal cell polarity is essential for neural tube closure [13]. In particular, it is very well known that JAG1 is part of the NOTCH cell pathway [14] and that NOTCH signaling has an essential impact on apical/basal cell polarity [13]. The most updated data indicate that Notch signaling plays a role in both differentiation and the organization of development in the central nervous system. > To the best of our knowledge, this is the first description of a neural tube defect as an onset sign of Alagille in a pediatric patient. The vast majority of children affected by this condition display an association between cholestasis (96%) and congenital heart malformation, while the most common kind of heart involvement is pulmonic stenosis (67% of patients [15]). Spina bifida occulta has already been described in patients clinically affected by Alagille syndrome [16]. In these cases, already published, no mention about mutation(s) nor genes involved has never been provided. Instead, here we describe for the first time ever a possible cause for this phenotype, including a case of spina bifida occulta in the apparent absence of other major environmental and genetic causes. It is remarkable that the same dose of folic acid had been taken by the mother for the first trimester of gestation in the previous pregnancy, which resulted in a healthy male newborn without any clinical signs of neural tube defect. > In the present case, the clinical picture was characterized at its onset by congenital spina bifida occulta and cyanotic heart disease: this is not a common association to lead the pediatrician to the suspicion of Alagille syndrome. This condition is more commonly suspected due to the association between cholestasis and congenital heart malformations.

[11] Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

  • Authors: G. Vitale, A. Mattiaccio, A. Conti, Laura Turco, M. Seri et al.
  • Year: 2022
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/36d42bac26fd444f619e3b6487c8a13a224b910e
  • DOI: 10.3390/cancers14143421
  • PMID: 35884482
  • PMCID: 9322180
  • Citations: 20
  • Influential citations: 1
  • Summary: The available data on FIC-related hepatobiliary cancers is reviewed, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
  • Evidence snippets:
  • Snippet 1 (score: 0.356) > Historically, inherited cholestatic diseases such as PFIC and Alagille syndrome are considered neonatal and pediatric disorders, characterized by a defect in BAs transport or structure of tight junctions at the level of hepatocyte, secondarily impairing bile excretion and liver accumulation resulting in itching, hepatocyte injury and cirrhosis [14]. Eight different PFIC types have now been described, other than MYO5B, which is another gene responsible for a clinical picture similar to PFICs. > Figure 1 summarizes the proteins involved in BAs metabolism and transport, their role and their position in hepatocytes, biliocytes and intestinal cells. > The eight genes involved in these mendelian diseases are present on OMIM ® . Table 1 summarizes genes, year of discovery, and main phenotypes correlated to PFIC including association with the HBCs cases: > -ATP8B1 gene (PFIC1): it is responsible for the synthesis of a lipid flippase, able to maintain the asymmetry of the cell membrane by the translocation of phospholipids from the exoplasmic to the cytoplasmic leaflet, having a protective role against excessive concentrations of BAs [14]; -ABCB11 gene (PFIC2): coding for the bile export pump (BSEP), ABCB11 regulates the excretion of monovalent BAs from hepatocytes to bile canaliculi against a concentration gradient. The accumulation of BAs in hepatocytes is induced by a less expression or a malfunction of BSEP, resulting in cellular injury and alterations of the enterohepatic pathway of BAs [14]; -ABCB4 gene (PFIC3): alterations of the MDR3 glycoprotein, a phosphatidylcholine flippase sited in the canalicular membrane of hepatocytes, lead to the disease; MDR3 protein carries phosphatidylcholine from the hepatocytes into the bile canaliculus, protecting the cholangiocytes from the detergent activity of BAs and reducing cellular injury.

[12] Gene Therapy for Acquired and Genetic Cholestasis

  • Authors: Javier Martínez-García, Angie Molina, G. González-Aseguinolaza, N. Weber, C. Smerdou
  • Year: 2022
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/ce8b7aeadf153ca3ed48a16677ba2a92d831ab62
  • DOI: 10.3390/biomedicines10061238
  • PMID: 35740260
  • PMCID: 9220166
  • Citations: 8
  • Influential citations: 1
  • Summary: Important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.
  • Evidence snippets:
  • Snippet 1 (score: 0.356) > ALGS arises due to mutations in genes involved in the Notch signaling pathway, such as JAG1 and NOTCH2, and the majority of patients present cholestasis and a deficiency of bile ducts [21]. CTX is caused by mutations in the CYP27A1 gene, resulting in impaired BA biosynthesis The role of BSEP in the functioning of the hepatobiliary system is very important, as mutations in different genes involved in BA metabolism and transport, such as ABCB11, NR1H4, and MYO5B causing its deficiency, cause PFIC [14][15][16]. In addition, depending on the severity of the disease, inherited intrahepatic cholestasis resulting from mutations in ATP8B1 or ABCB11 can be classified as either PFIC1 or 2, respectively, or benign recurrent intrahepatic cholestasis (BRIC) 1 or 2, respectively. Sometimes it is clinically difficult to discern between PFIC and BRIC because, in both cases, patients may present mild cholestasis with long-term complications [17]. In addition, some missense mutations in less conserved regions of the ABCB11 and ABCB4 genes promote the development of more moderate variants of cholestasis such as BRIC2, ICP, cholesterol cholelithiasis, drug-induced cholestasis, adult biliary cirrhosis, transient neonatal cholestasis, and others [18,19]. In addition, mutations in cholangiocyte transporter genes (e.g., the cystic fibrosis transmembrane conductance regulator (CFTR) gene) can cause cholestasis. In fact, a direct association between cystic fibrosis and cholestatic conditions, such as bile duct complications, gallstones, and primary sclerosing cholangitis, has been observed due to mutations in CFTR [20]. Other genetic multisystemic diseases associated with cholestatic disorders include Alagille syndrome (ALGS) and cerebrotendinous xanthomatosis (CTX).

[13] Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations

  • Authors: E. Andersson, Indira V. Chivukula, Simona Hankeová, Marika Sjöqvist, Y. Tsoi et al.
  • Year: 2017
  • Venue: Gastroenterology
  • URL: https://www.semanticscholar.org/paper/66b377d07a4fb3b1eae49d5eb74694afba76ab7b
  • DOI: 10.1053/j.gastro.2017.11.002
  • PMID: 29162437
  • PMCID: 7007299
  • Citations: 105
  • Influential citations: 2
  • Summary: In mice, expression of a missense mutant of Jag1 (Jag1Ndr) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology.
  • Evidence snippets:
  • Snippet 1 (score: 0.354) > Background & Aims Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. Methods Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. Results Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG1Ndr, compared with

[14] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

  • Authors: Hao Xiong, Jinsheng Guo
  • Year: 2025
  • Venue: Pharmaceuticals
  • URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
  • DOI: 10.3390/ph18040507
  • PMID: 40283943
  • PMCID: 12030350
  • Citations: 8
  • Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.351) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[15] Research trends and hotspots of adult Alagille syndrome: a bibliometric analysis

  • Authors: Qing Liu, Jie Yang, Wentian Liu, Chao Sun
  • Year: 2025
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/49e60bed104eaacbaf2e31762fc85839fb6524c8
  • DOI: 10.1186/s13023-025-03855-5
  • PMID: 40597401
  • PMCID: 12210516
  • Citations: 1
  • Summary: This study systematically summarizes the results of adult ALGS researches, describes and predicts research hotspots and trends on a global scale, which may be helpful for clinicians and researchers to improve their clinical understanding of this disease, and provide a valuable reference for future intensive investigation.
  • Evidence snippets:
  • Snippet 1 (score: 0.351) > Research trends and hotspots of adult Alagille syndrome: a bibliometric analysis

[16] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 2
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.350) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[17] Notch1 siRNA and AMD3100 Ameliorate Metabolic Dysfunction-Associated Steatotic Liver Disease

  • Authors: Chunli Zhu, Yiheng Cheng, Lei Yang, Yifu Lyu, Jingjing Li et al.
  • Year: 2025
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/f3a6939b33db32d6c141825ae843fbc27c1d1ad8
  • DOI: 10.3390/biomedicines13020486
  • PMID: 40002899
  • PMCID: 11853639
  • Citations: 2
  • Summary: This work demonstrated that in liver cells, siNotch1 combined with AMD3100 not only directly modulated macrophages by downregulating multiple pathways downstream of Notch, exerting anti-inflammatory, anti-migration, and switch of macrophage phenotype, but also modulated macrophage phenotypes through inhibiting NET release.
  • Evidence snippets:
  • Snippet 1 (score: 0.348) > Metabolic dysfunction-associated steatotic liver disease (MASLD), renamed from non-alcoholic liver disease (NAFLD), is considered one of the most common causes of chronic liver diseases, including progression of hepatic steatosis, metabolic dysfunctionassociated steatohepatitis (MASH), fibrosis, and hepatocellular carcinoma (HCC) [1,2]. Meanwhile, MASLD is a multisystem disease with some extrahepatic complications like cardiovascular disease (CVD), type 2 diabetes mellitus, and chronic kidney disease [3]. MASLD represents a significant and progressively increasing global health and economic burden, while prevalence of MASLD continues to increase substantially worldwide [4]. The good news is that the FDA approved the first drug for the treatment of MASH, Rezdiffra, in 2024, but the long-term efficacy of the drug is still being studied and evaluated [5]. Moreover, other promising drugs targeting mechanisms of MASLD are still under clinical trials. Apart from developing new drugs, considering the complex pathogenesis of MASLD, it is necessary to propose more clinical protocols for drug combination to treat MASLD, as efficacy can be increased and side effects can be reduced in this way [6]. > The Notch signaling pathway is extremely evolutionarily conserved and is extensively involved in various diseases of the nervous, immune, and cardiovascular systems [7]. In MASLD progression, the Notch signaling pathway is associated with hepatic lipid accumulation, insulin resistance (IR), oxidative stress (OS), fibrogenesis, and autophagy progression in MASLD [8]. Specifically, the Notch signaling pathway is involved in the activation and effect of pro-inflammatory macrophages, and it directly regulates the transcription of pro-inflammatory signature genes, such as Il6, Il12b, and Nos2 [9]. In monocytes, the Notch signaling pathway plays a crucial role in cell migration and differentiation [10], and it also mediates the transition between the Ly6C high inflammatory phenotype and the Ly6C low circulating surveillance phenotype through mechanisms similar to those in macrophages [11].

[18] 20p chromosome inverted duplication syndrome with phenotypes of congenital heart disease, anorectal malformation and megacolon

  • Authors: Guangxian Yang, Wenwen Fan, Ni Yin, Zhiping Tan
  • Year: 2024
  • Venue: BMJ Case Reports
  • URL: https://www.semanticscholar.org/paper/161ebed1bf25e3dd2e6a43067e6bba95a6cb9bd9
  • DOI: 10.1136/bcr-2024-261019
  • PMID: 39510612
  • Summary: A middle childhood case of 20p chromosome inverted duplication deletion syndrome is reported, characterised by intellectual disability, backward movement, unique facial features, congenital heart disease: ventricular septal defect, patent foramen ovale, pulmonary hypertension and congenital anorectal malformation.
  • Evidence snippets:
  • Snippet 1 (score: 0.345) > Cholestasis is caused by a lack of intrahepatic bile ducts; renal malformations (mainly renal dysplasia) exist in approximately 39% of these patients. 11 Rodriguez et al 12 first reported the ARM phenotype of Alagille syndrome in a male at late adolescence with signs of embryonic tail dysplasia: anal atresia, rectourethral fistula, lumbosacral abnormalities and right renal dysplasia. More than 95% of patients with ALGS1 have heart defects, especially in the right-ventricular system (from mild peripheral pulmonary stenosis to severe tetralogy of fallot involving the right ventricle and pulmonary artery). The JAG1 gene is involved in the notch signalling pathway, regulation of which is essential for the formation of ventricular-outflow tracts and ventricular trabeculae in the embryonic heart. 13 Our patient's severe jaundice in the neonatal period and CHD (especially VSD) might be strongly related to the JAG1 gene. Bone morphogenetic protein 2 (BMP2; OMIM #112 261), 14 located at 20p12.3, is a gene encoding the transforming growth factor beta (TGF-β) superfamily. The TGF-β signalling pathway constitutes a large cytokine superfamily that plays an important role in regulating the growth, migration, proliferation, differentiation and apoptosis of cells in a series of processes relating to cell differentiation and growth. Variations of BMP2 are associated with the disease brachydactyly type A2 (OMIM #112 600), facial dysmorphism, short stature and skeletal anomalies with or without cardiac anomalies (SSFSC1; OMIM #617 877). This child's toe and cardiac abnormalities might also be related to this gene. > In addition, sex-determining region Y-related 3-hydroxy-3-methylglutaryl box 12 (SOX12; OMIM #609 147) and neurensin 2 (NRSN2; OMIM #610 666), which are located in the 20p subtelomere region, are associated with developmental delay, especially of language. 15

[19] Alagille Syndrome: A Case Report

  • Authors: Madhabi Baidya, Syed Shafi Ahmed, Salauddin Mahmud
  • Year: 2022
  • Venue: Dhaka Shishu (Children) Hospital Journal
  • URL: https://www.semanticscholar.org/paper/bcd83bafc2117c53a71fb2633b40bda1331325c3
  • DOI: 10.3329/dshj.v37i1.59120
  • Summary: Abstract not available DS (Child) H J 2021; 37(1): 71-73
  • Evidence snippets:
  • Snippet 1 (score: 0.344) > Alagille syndrome is an autosomal recessive disorder which occur because of notch signaling pathway defects, primarily as a result of JAG1 mutation (ALG type 1), but it conjointly occurs seldom because of neurogenic locus notch homolog protein (NOTCH2) mutation (ALG type 2). 1,2 The syndrome and severity of Alagille can vary widely, often in the same family, from person to person. Some people may have mild form, while others may have more severe form. It is characterized by abnormalities in the liver, heart, eyes, face and skeleton. The main clinical manifestation of Alagille syndrome is cholestasis resulting from paucity of intrahepatic bile ducts and it is commonly associated with other clinical signs: heart disease, skeletal abnormalities, ocular abnormalities and facial dysmorphism. 3 pical facial alterations include sunken eyes, wide forehead, prominent chin, bulbous nose and small or malformed ears. Laboratory findings are increased blood levels of bile acids and direct bilirubin; increased transaminase, alkaline phosphatase, and gamma-glutamyltransferase activities and hypercholesterolemia. Histological findings are the presence of bile pigments in the cytoplasm of hepatocytes and in the lumen of bile canaliculi, ductules and ducts often associated with secondary cell injury. 4,5 veral diseases can present cholestasis as a symptom; therefore, differential diagnosis continues to pose a challenge for pediatrician. In this case report, we present a patient in whom diagnosis of Alagille syndrome was done. It is important to be familiar with Alagille syndrome, so that its diagnosis can be suspected when a patient presents specific physical and morphological features, in addition to jaundice.

[20] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.343) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.