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Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1 Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1 Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1 Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1 -/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1 Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1 +/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1 -/- mice with Jag1 Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1 -/- mice with Jag1 +/+ lymphocytes. Finally, the Jag1 Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS., Competing Interests: Disclosure and competing interests statement The authors declare no competing interests. ERA has formerly collaborated with Travere, and Moderna, with no personal remuneration and no conflict of interest., (© 2024. The Author(s).)

Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disease with a high interindividual variability. The two causative genes JAG1 and NOTCH2 are expressed during kidney development, can be reactivated during adulthood kidney disease, and Notch signalling is essential for vascular morphogenesis and remodelling in mice. Liver disease is the most frequent and severe involvement; neonatal cholestasis occurs in 85% of cases, pruritus in 74%, xanthomas in 24% of cases, and the cumulative incidences of portal hypertension and liver transplantation are 66% and 50% respectively at 18 years of age. Stenosis/hypoplasia of the branch pulmonary arteries is the most frequent vascular abnormality reported in ALGS. Kidney involvement is present in 38% of patients, and can reveal the disease. Congenital anomalies of the kidney and urinary tract is reported in 22% of patients, hyperchloremic acidosis in 9%, and glomerulopathy and/or proteinuria in 6%. A decreased glomerular filtration rate is reported in 10% of patients and is more frequent after liver transplantation for ALGS than for biliary atresia. Kidney failure has been frequently reported in childhood and adulthood. 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. ALGS patients require kidney assessment at diagnosis, long-term monitoring of kidney function and early detection of vascular complications, notably if they have undergone liver transplantation, to prevent progression of chronic kidney disease and vascular complications, which account for 15% of deaths at a median age of 2.2 years in the most recent series., (© 2024. The Author(s).)

Haploinsufficiency of JAG1 is the primary cause of Alagille syndrome (ALGS), a rare, multisystem disorder. The identification of JAG1 intronic variants outside of the canonical splice region as well as missense variants, both of which lead to uncertain associations with disease, confuses diagnostics. Strategies to determine whether these variants affect splicing include the study of patient RNA or minigene constructs, which are not always available or can be laborious to design, as well as the utilization of computational splice prediction tools. These tools, including SpliceAI and Pangolin, use algorithms to calculate the probability that a variant results in a splice alteration, expressed as a Δ score, with higher Δ scores (>0.2 on a 0-1 scale) positively correlated with aberrant splicing. We studied the consequence of 10 putative splice variants in ALGS patient samples through RNA analysis and compared this to SpliceAI and Pangolin predictions. We identified eight variants with aberrant splicing, seven of which had not been previously validated. Combining these data with non-canonical and missense splice variants reported in the literature, we identified a predictive threshold for SpliceAI and Pangolin with high sensitivity (Δ score >0.6). Moreover, we showed reduced specificity for variants with low Δ scores (<0.2), highlighting a limitation of these tools that results in the misidentification of true splice variants. These results improve genomic diagnostics for ALGS by confirming splice effects for seven variants and suggest that the integration of splice prediction tools with RNA analysis is important to ensure accurate clinical variant classifications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To explore patterns of disease expression in Alagille syndrome (ALGS)., Methods: Patients underwent ophthalmic examination, optical coherence tomography (OCT) imaging, fundus intravenous fluorescein angiography (IVFA), perimetry and full-field electroretinograms (ffERGs). An adult ALGS patient had multimodal imaging and specialized perimetry., Results: The proband (P1) had a heterozygous pathogenic variant in JAG1 ; (p.Gln410Ter) and was incidentally diagnosed at age 7 with a superficial retinal hemorrhage, vascular tortuosity, and midperipheral pigmentary changes. The hemorrhage recurred 15 months later. Her monozygotic twin sister (P2) had a retinal hemorrhage at the same location at age 11. Visual acuities for both patients were 20/30 in each eye. IVFA was normal. OCT showed thinning of the outer nuclear in the peripapillary retina. A ffERG showed normal cone-mediated responses in P1 (rod-mediated ERGs not documented), normal ffERGs in P2. Coagulation and liver function were normal. An unrelated 42-year-old woman with a de-novo pathogenic variant (p. Gly386Arg) in JAG1 showed a similar pigmentary retinopathy and hepatic vascular anomalies; rod and cone function was normal across large expanses of structurally normal retina that sharply transitioned to a blind atrophic peripheral retina., Conclusion: Nearly identical recurrent intraretinal hemorrhages in monozygotic twins with ALGS suggest a shared subclinical microvascular abnormality. We hypothesize that the presence of large areas of functionally and structurally intact retina surrounded by severe chorioretinal degeneration, is against a predominant involvement of JAG1 in the function of the neurosensory retina, and that instead, primary abnormalities of chorioretinal vascular development and/or homeostasis may drive the peculiar phenotypes.

Chronic cholestasis due to heritable causes is usually diagnosed in childhood. However, many cases can present and survive into adulthood. The time course varies considerably depending on the underlying etiology. Laboratory data usually reveal elevated conjugated hyperbilirubinemia, alkaline phosphatase, and gamma-glutamyl transpeptidase. Patients may be asymptomatic; however, when present, the typical symptoms are pruritus, jaundice, fatigue, and alcoholic stools. The diagnostic methods and management required depend on the underlying etiology. The development of genome-wide associated studies has allowed the identification of specific genetic mutations related to the pathophysiology of cholestatic liver diseases. The aim of this review was to highlight the genetics, clinical pathophysiology, presentation, diagnosis, and treatment of heritable etiologies of chronic cholestatic liver disease., Competing Interests: GYW has been an Editor-in-Chief of Journal of Clinical and Translational Hepatology since 2013. The other author has no conflict of interests related to this publication., (© 2024 Authors.)

Background: Alagille syndrome (ALGS) is a multisystem genetic disorder frequently characterized by hepatic manifestations. This study analyzed the clinical, pathological, and molecular genetic features of ALGS to improve the efficiency of clinical diagnosis., Methods: We retrospectively analyzed the clinical manifestations, pathological examination findings, and genetic testing results of 17 children diagnosed with ALGS based on the revised criteria and hospitalized at our center from January 2012 to January 2022., Results: The clinical manifestations are as follows: Cholestasis (16/17, 94%), characteristic facies (15/17, 88%), heart disease (12/16, 75%), butterfly vertebrae (12/17, 71%) and posterior embryotoxon (7/12, 58%). Among the 15 patients who underwent liver pathology examination, 13 (87%) were found to have varying degrees of bile duct paucity. Genetic testing was performed on 15 children, and pathogenic variants of the jagged canonical Notch ligand 1 (JAG1) gene were identified in 13 individuals, including 4 novel variants. No pathogenic variant in the notch homolog 2 (NOTCH2) gene were identified, and 2 children exhibited none of the aforementioned gene pathogenic variants. The median follow-up duration was 7 years. Of the remaining 15 patients (excluding 2 lost to follow-up), 11 remained stable, 4 deteriorated, and no patient died during the follow-up period., Conclusions: Among children diagnosed with ALGS, cholestasis stands as the most common feature. To minimize the risk of misdiagnosis, genetic testing should be performed on children exhibiting cholestasis, followed by the application of the revised diagnostic criteria for ALGS. While pharmacological therapy has shown effectiveness for ALGS patients, liver transplantation may be considered in instances of severe pruritus., (© 2024. The Author(s).)

Pathogenic variants in the JAG1 gene are a primary cause of the multi-system disorder Alagille syndrome. Although variant detection rates are high for this disease, there is uncertainty associated with the classification of missense variants that leads to reduced diagnostic yield. Consequently, up to 85% of reported JAG1 missense variants have uncertain or conflicting classifications. We generated a library of 2,832 JAG1 nucleotide variants within exons 1-7, a region with a high number of reported missense variants, and designed a high-throughput assay to measure JAG1 membrane expression, a requirement for normal function. After calibration using a set of 175 known or predicted pathogenic and benign variants included within the variant library, 486 variants were characterized as functionally abnormal (n = 277 abnormal and n = 209 likely abnormal), of which 439 (90.3%) were missense. We identified divergent membrane expression occurring at specific residues, indicating that loss of the wild-type residue itself does not drive pathogenicity, a finding supported by structural modeling data and with broad implications for clinical variant classification both for Alagille syndrome and globally across other disease genes. Of 144 uncertain variants reported in patients undergoing clinical or research testing, 27 had functionally abnormal membrane expression, and inclusion of our data resulted in the reclassification of 26 to likely pathogenic. Functional evidence augments the classification of genomic variants, reducing uncertainty and improving diagnostics. Inclusion of this repository of functional evidence during JAG1 variant reclassification will significantly affect resolution of variant pathogenicity, making a critical impact on the molecular diagnosis of Alagille syndrome., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Alagille syndrome (ALGS) is a rare autosomal dominant genetic disease caused by pathogenic variants in two genes: Jagged Canonical Notch Ligand 1 ( JAG1 ) and Notch Receptor 2 ( NOTCH2 ). It is characterized by phenotypic variability and incomplete penetrance with multiorgan clinical signs., Methods: Using Next Generation Sequencing (NGS), we analyzed a panel of liver-disease-related genes in a population of 230 patients with cholestasis and hepatopathies. For the rare variants, bioinformatics predictions and pathogenicity classification were performed., Results: We identified eleven rare NOTCH2 variants in 10 patients, two variants being present in the same patient. Ten variants had never been described before in the literature. It was possible to classify only two null variants as pathogenic, whereas the most of variants were missense (8 out of 11) and were classified as uncertain significance variants (USVs). Among patients with ALGS suspicion, two carried null variants, two carried variants predicted to be pathogenic by bioinformatics, one carried a synonymous variant and variants in glycosylation-related genes, and two carried variants predicted as benign in the PEST domain., Conclusions: Our results increased the knowledge about NOTCH2 variants and the related phenotype, allowing us to improve the genetic diagnosis of ALGS.

Introduction: Alagille syndrome (ALGS) is a rare, genetic, multisystem disorder commonly associated with cholestatic liver disease; patients with ALGS may experience elevated serum bile acids and severe pruritus with associated impaired sleep. The ileal bile acid transporter (IBAT) is located on the luminal surface of enterocytes in the terminal ileum; this transport protein mediates resorption of conjugated bile acids for recirculation back to the liver. Inhibition of IBAT disrupts the enterohepatic circulation and leads to fecal elimination of bile acids., Areas Covered: Here, the role of odevixibat as a novel, nonsurgical approach to interrupting the enterohepatic circulation from the intestine by inhibition of IBAT is reviewed, specifically in reference to currently available data on pharmacologic IBAT inhibition. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of cholestatic liver diseases in children including ALGS., Expert Opinion: Odevixibat or IBAT inhibitor should be considered as a first-line treatment for ALGS to improve pruritis, quality of life and liver-related outcomes including absence of liver transplant, surgical biliary diversion, hepatic decompensation, and death.

Purpose: Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with highly variable expression. Intracranial arterial and venous anomalies have a reported prevalence of 30-40% and can increase the risk of stroke by 16%. Few reports document the frequency and evolution of cerebrovascular abnormalities (CVAs) in children with ALGS. We aimed to define the spectrum, frequency, and evolution of CVAs in a series of children with ALGS using magnetic resonance angiography (MRA)., Methods: We conducted a single-center, retrospective study in a large tertiary pediatric hospital. CVAs were grouped into 4 categories: 1) Stenosis or narrowing; 2) Aneurysms and ectasias; 3) Tortuosity; and 4) Vascular anomalies and anatomical variants., Results: Thirty-two children met the inclusion criteria. The median age at initial diagnosis was 6 (3.8-10.3) years. Thirteen (40%) had follow-up MRI at a mean of 55 (31.5-66) months. Eighteen (56%) had CVAs; the most frequent fell into group 1 (n = 12, 37.5%). CVAs were stable over time, except for one patient with Moyamoya arteriopathy (MMA). One patient developed a transient ischemic attack secondary to an embolic event. Three (9.3%) had microhemorrhages at the initial diagnosis secondary to Tetralogy of Fallot. Another patient had recurrent subdural hematomas of unknown cause., Conclusion: CVAs were stable except in the presence of MMA. Vascular strokes, which are reported in older patients with ALGS, were not a common feature in children under 16 years of age, either at presentation or over the 31.5-66 month follow-up period., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alagille syndrome is caused by mutations in genes involved in NOTCH signaling, specifically JAG1 and NOTCH2, and is associated with a high rate of peripheral pulmonary artery stenosis. In this study, we report the case of an infant with Alagille syndrome caused by a JAG1 mutation, who succumbed to acute exacerbation of right heart failure due to severe peripheral pulmonary artery stenosis. The autopsy revealed that the peripheral pulmonary arteries were significantly stenosed, exhibiting hypoplasia and thickened vessel walls. Histological examination of the pulmonary artery walls showed a decrease in smooth muscle cells in the tunica media and an increase in collagen and elastic fibers, although the intrapulmonary arteries were intact. These findings are important for understanding the pathogenesis of Alagille syndrome and developing treatment strategies for peripheral pulmonary artery stenosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: In this paper, we share our single-center experience of successful multidisciplinary management of patients with Alagille syndrome. In addition, we aim to highlight the need for an Alagille program for effectively managing these patients, in general, and particularly peripheral pulmonary artery stenosis associated with this syndrome. Study Design: This is a retrospective review of six children with Alagille syndrome and advanced liver involvement who underwent pulmonary artery reconstruction between 2021 and 2022. Cardiac diagnosis, co-existing liver disease burdens, management approach, and short-term outcomes were analyzed. Results: All the patients underwent one-stage extensive bilateral branch pulmonary rehabilitation. Concomitant procedures included repair of tetralogy of Fallot in one patient and repair of supravalvar pulmonary artery stenosis in two. One patient had balloon pulmonary branch angioplasty before surgery. In all patients, there was a decrease in right ventricular systolic pressure post-operatively. Three patients underwent liver transplantation for pre-existing liver dysfunction. At a median 3-year follow-up, all the patients were alive with their right ventricular systolic pressure less than half of their systemic systolic pressure. One patient underwent balloon angioplasty due to new and recurrent left pulmonary artery stenosis 13 months after surgery. Conclusion: Pulmonary arteries can be successfully rehabilitated surgically in the presence of complex branch disease. Patients with advanced liver disease can undergo successful complex pulmonary artery reconstruction, which can facilitate their future liver transplantation course. A multidisciplinary team approach is a key for successful management of Alagille patients.

Alagille syndrome is an autosomal dominant and multisystemic disease that generally manifests itself with intrahepatic bile ducts paucity, chronic cholestasis, xanthomas and with other less frequent clinical manifestations such as congenital heart disease, skeletal abnomalies, ophthalmic, vascular, renal and growth failure. Symptoms can be subclinical or very severe. Is caused by various genetic mutations and the majority of patients have a detectable mutation in JAG1 (90%), the remainder have mutations in NOTCH2. The diagnosis is molecular and the incidence is approximately 1 in 30,000 - 50.000. Patient management can be very complex and treatment depends on the district affected and on the symptoms. In more serious cases, with terminal liver disease, liver transplantation is used. We describe a case with main bile duct hypoplasia, intrahepatic bile ducts paucity, cholestasis and gallbladder dimorphism associated with renal malrotation and butterfly vertebrae., (© 2024 Published by Elsevier Inc. on behalf of University of Washington.)

Competing Interests: None disclosed.

Introduction: Alagille syndrome (AGS) is a genetic disease with multisystemic affection, including ocular manifestations. Recently, a high frequency of posterior segment findings, including macular changes, has been reported. This publication aims to report an unusual finding of macular atrophy and a focal choroidal excavation in a patient with JAG1 related AGS., Methods: Case report., Results: This publication describes an atypical presentation of focal choroidal excavation (FCE) and unilateral macular atrophy in a 7-year-old male with Alagille syndrome (AGS). Genetic analysis revealed a pathogenic variant in the JAG1 gene. Ophthalmological examination and imaging findings demonstrated characteristic ocular manifestations of AGS, including posterior embryotoxon, chorioretinal atrophy, and thinning of the choroid., Conclusion: The presence of FCE in AGS is uncommon, and the underlying mechanisms remain unclear. Further exploration of similar cases is necessary to better understand the evolution and visual prognosis in patients with AGS and FCE.

Background: Alagille syndrome (ALGS) is a multisystem disorder involving at least three systems among the liver, heart, skeleton, face, and eyes. Common cardiac associations include pulmonary artery stenosis/atresia, atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of fallot (ToF). Coarctation of aorta (CoA), renal and intracranial arteries are commonly involved vessels in Alagille syndrome. We present two cases with rare cardiovascular manifestations of Alagille syndrome. Case description ., Case 1: A 25-year-old female with a history of Alagille syndrome presented to the cardiologist office for progressive exertional dyspnoea, orthopnoea, and palpitations. She was tachycardiac on examination and had an apical diastolic rumble. A transthoracic echocardiogram (TTE) showed a left ventricular ejection fraction (LVEF) of 60% and parachute mitral valve (PMV) with severe mitral stenosis. A transoesophageal echocardiogram (TOE) showed insertion of chordae into the anterolateral papillary muscle, severe mitral stenosis with a valve area of 0.7 cm. She was referred to a congenital heart disease specialist and underwent robotic mitral valve replacement with improvement in her symptoms., Case 2: A 27-year-old female with known Alagille syndrome and resistant hypertension presented to the cardiologist office due to progressive exertional dyspnoea for a year. She was hypertensive and had a new 2/6 systolic ejection murmur along the left upper sternal border. TTE revealed an LVEF of 60% and pulmonary artery pressure of 19 mmHg. A CoA was suspected distal to the left subclavian artery due to a peak gradient of 38 mmHg. Cardiac magnetic resonance (CMR) imaging ruled out CoA, and diffuse narrowing of the descending thoracic aorta measuring 13-14 mm in diameter was noted. The patient was referred to a congenital heart disease specialist for further management., Conclusion: PMV presenting as mitral stenosis and mid-aortic syndrome are not commonly described anomalies in association with Alagille syndrome. TTE, TOE and CMR played a key role in diagnosis and management of these patients., Learning Points: Alagille syndrome (ALGS) is a complex multisystem disorder involving the liver, heart, skeleton, face, and eyes. Cardiovascular involvement occurs in up to 95% of the patients.Common cardiac associations include pulmonary artery stenosis/atresia, atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of fallot (ToF).A parachute mitral valve (PMV) presenting as mitral stenosis and mid-aortic syndrome is not commonly described anomalies in association with ALGS. Here, we present such rare cases., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2024.)

Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert. Bile acid (BA) synthesis and excretion, the formation and flow of bile, and the enterohepatic reuptake of BAs all function to maintain the circulation of BAs, a key molecule in lipid digestion, metabolic and cellular signaling, and, as discussed in the review, a crucial mediator in the pathogenesis of cholestasis. Disruption of one or several of these steps can result in the accumulation of toxic BAs in bile ducts and hepatocytes leading to inflammation, fibrosis, and, over time, biliary and hepatic cirrhosis. Biliary atresia, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and Alagille syndrome are four of the most common pediatric cholestatic conditions. Through understanding the commonalities and differences in these diseases, the important cellular mechanistic underpinnings of cholestasis can be greater appreciated.

Rationale: Alagille syndrome is a rare genetic disorder with dental and facial abnormalities in the head-and-neck area. It is autosomal dominant and occurs in approximately 1 in 100,000 people. No cases of Alagille Syndrome (ALGS) with mandibular hypoplasia and temporomandibular joint ankyloses (TMJa) have been reported to date., Patient Concerns and Diagnosis: A 3-year-old female patient suffering from ALGS came to our hospital affected by unilateral mandibular hypoplasia and TMJa with severe limitation of mouth opening (maximal interincisal distance [MID] of 2 mm)., Treatment: A two-phase surgical management approach was undertaken based on computed tomography scans and the patient's age. The first phase involved mandibular distraction, followed by arthroplasty with amniotic human membrane placement., Outcomes: After immediate post-surgery rehabilitation, the patient showed good mandibular function with no complications after 15 months. MID was 20 mm., Take-Away Lessons: This is a rare and interesting case with no previous literature reports. The use of amniotic membranes in surgical management adds further significance., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Annals of Maxillofacial Surgery.)

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Tricuspid atresia (TA) is a rare congenital heart condition that presents with a complete absence of the right atrioventricular valve. Because of the rarity of familial and/or isolated cases of TA, little is known about the potential genetic abnormalities contributing to this condition. Potential responsible chromosomal abnormalities were identified in exploratory studies and include deletions in 22q11, 4q31, 8p23, and 3p as well as trisomies 13 and 18. In parallel, potential culprit genes include the ZFPM2, HEY2, NFATC1, NKX2-5, MYH6, and KLF13 genes. The aim of this chapter is to expose the genetic components that are potentially involved in the pathogenesis of TA in humans. The large variability in phenotypes and genotypes among cases of TA suggests a genetic network that involves many components yet to be unraveled., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in either the JAG1 gene (ALGS type 1) or the NOTCH2 gene (ALGS type 2). The disease has been difficult to diagnose and treat due to its muti-system clinical presentation, variable expressivity, and prenatal onset for some of the features. The generation of this iPSC line (TRNDi032-A) carrying a heterozygous mutation, p.Cys682Leufs*7 (c.2044dup), in the JAG1 gene provides a means of studying the disease and developing novel therapeutics towards patient treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wei Zheng reports financial support was provided by Travere Therapeutics Inc. Karsten Baumgaertel reports a relationship with Travere Therapeutics Inc that includes: employment., (Published by Elsevier B.V.)

Purpose of Review: Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies., Recent Findings: Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This study focuses on Na(+)-taurocholate cotransporting polypeptide (NTCP) deficiency to analyze and investigate the value of the serum bile acid profile for facilitating the diagnosis and differential diagnosis. Methods: Clinical data of 66 patients with cholestatic liver diseases (CLDs) diagnosed and treated in the Department of Pediatrics of the First Affiliated Hospital of Jinan University from early April 2015 to the end of December 2021 were collected, including 32 cases of NTCP deficiency (16 adults and 16 children), 16 cases of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), 8 cases of Alagille syndrome, and 10 cases of biliary atresia. At the same time, adult and pediatric healthy control groups (15 cases each) were established. The serum bile acid components of the study subjects were qualitatively and quantitatively analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry. The data were plotted and compared using statistical SPSS 19.0 and GraphPad Prism 5.0 software. The clinical and bile acid profiles of children with NTCP deficiency and corresponding healthy controls, as well as differences between NTCP deficiency and other CLDs, were compared using statistical methods such as t-tests, Wilcoxon rank sum tests, and Kruskal-Wallis H tests. Results: Compared with the healthy control, the levels of total conjugated bile acids, total primary bile acids, total secondary bile acids, glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were increased in NTCP deficiency patients ( P < 0.05). Compared with adults with NTCP deficiency, the levels of total conjugated bile acids and total primary bile acids were significantly increased in children with NTCP deficiency ( P < 0.05). The serum levels of taurochenodeoxycholic acid, glycolithocholate, taurohyocholate, and tauro-α-muricholic acid were significantly increased in children with NTCP deficiency, but the bile acid levels such as glycodeoxycholic acid, glycolithocholate, and lithocholic acid were decreased ( P < 0.05). The serum levels of secondary bile acids such as lithocholic acid, deoxycholic acid, and hyodeoxycholic acid were significantly higher in children with NTCP deficiency than those in other CLD groups such as NICCD, Alagille syndrome, and biliary atresia ( P < 0.05). Total primary bile acids/total secondary bile acids, total conjugated bile acids/total unconjugated bile acids, taurocholic acid, serum taurodeoxycholic acid, and glycodeoxycholic acid effectively distinguished children with NTCP deficiency from other non-NTCP deficiency CLDs. Conclusion: This study confirms that serum bile acid profile analysis has an important reference value for facilitating the diagnosis and differential diagnosis of NTCP deficiency. Furthermore, it deepens the scientific understanding of the changing characteristics of serum bile acid profiles in patients with CLDs such as NTCP deficiency, provides a metabolomic basis for in-depth understanding of its pathogenesis, and provides clues and ideas for subsequent in-depth research.

Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton, eyes, kidneys, and face and caused by pathogenic variants in the JAG1 or NOTCH2 gene. The variable expressivity of the clinical phenotype and the lack of genotype-phenotype correlations lead to significant diagnostic difficulties. Here we present an analysis of 18 patients with cholestasis who were diagnosed with ALGS. We used an NGS panel targeting coding exons of 52 genes, including the JAG1 and NOTCH2 genes. Sanger sequencing was used to verify the mutation in the affected individuals and family members. The specific facial phenotype was seen in 16/18 (88.9%). Heart defects were seen in 8/18 (44.4%) patients (pulmonary stenosis in 7/8). Butterfly vertebrae were seen in 5/14 (35.7%) patients. Renal involvement was detected in 2/18 (11.1%) cases-one patient had renal cysts, and one had obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only one had posterior embryotoxon (8.3%). A percutaneous liver biopsy was performed in nine cases. Bile duct paucity was detected in six/nine cases (66.7%). Two patients required liver transplantation because of cirrhosis. We identified nine novel variants in the JAG1 gene-eight frameshift variants (c.1619&#95;1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168&#95;3169delAG (p.R1056Sfs*51), c.2688delG (p.896CysfsTer49), c.164dupG (p.Cys55fs)) and one missense variant, c.2806T > G (p.Cys936Gly). None of the patients presented with NOTCH2 variants. In accordance with the classical criteria, only six patients could meet the diagnostic criteria in our cohort without genetic analysis. Genetic testing is important in the diagnosis of ALGS and can help differentiate it from other types of cholestasis.

Introduction: Alagille syndrome (ALGS) is an autosomal dominant, multisystem genetic disorder with wide phenotypic variability caused by mutations in the Notch signaling pathway, specifically from mutations in either the Jagged1 (JAG1) or NOTCH2 gene. The range of clinical features in ALGS can involve various organ systems including the liver, heart, eyes, skeleton, kidney, and vasculature. Despite the genetic mutations being well-defined, there is variable expressivity and individuals with the same mutation may have different clinical phenotypes., Areas Covered: While no clear genotype-phenotype correlation has been identified in ALGS, this review will summarize what is currently known about the genotype-phenotype relationship and how this relationship influences the treatment of the multisystemic disorder. This review includes discussion of numerous studies which have focused on describing the genotype-phenotype relationship of different organ systems in ALGS as well as relevant basic science and population studies of ALGS. A thorough literature search was completed via the PubMed and National Library of Medicine GeneReviews databases including dates from 1969, when ALGS was first identified, to February 2023., Expert Opinion: The genetics of ALGS are well defined; however, ongoing investigation to identify genotype-phenotype relationships as well as genetic modifiers as potential therapeutic targets is needed. Clinicians and patients alike would benefit from identification of a correlation to aid in diagnostic evaluation and management.

Background: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers., Methods: Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 μmol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≥ 85.5 μmol/L at the last follow-up., Results: We found that the concentrations of two poly-hydroxylated bile acids, tauro-2β,3α,7α,12α-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco- chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro-2β,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662-63.753), P = 0.002]., Conclusions: We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes., (© 2023. Children's Hospital, Zhejiang University School of Medicine.)

Background: Alagille syndrome (ALGS) is an autosomal dominant disease caused by JAG1 or NOTCH2 mutation. It is diagnosed by the presence of three out of five features: characteristic facies, posterior embryotoxon, peripheral pulmonary stenosis, vertebral defects, and interlobular bile duct paucity. This study aimed to review the prevalence, clinical presentations, diagnosis, treatment, and outcome of patients with ALGS., Materials and Methods: This is a retrospective review of patients with ALGS at the Pediatric Department, Salmaniya Medical Complex, Bahrain, between August 1994 and October 2022. The diagnosis was based on clinical, laboratory, radiological, histopathological, and genetic findings., Results: Five patients were found to have ALGS. The prevalence of ALGS in Bahrain was 1.04 patients per 100,000 (0.001%). Four were Bahraini and three were females. Median birth weight was 2.3 (2.3-2.5) kg. All patients presented at the time of birth with low birth weight, cholestatic jaundice, clay-colored stool, heart murmur, and dysmorphic facial features. All had congenital heart diseases, two had butterfly vertebrae, and one had posterior embryotoxon. All had elevated liver enzymes and normal abdominal ultrasound. Three had positive hepatobiliary iminodiacetic acid scan and one had bile duct paucity in liver biopsy. Three had intraoperative cholangiogram. Four were positive for JAG1 mutation. All received ursodeoxycholic acid and fat-soluble vitamins. Two required liver transplantation., Conclusion: ALGS is a rare disorder in Bahrain. Diagnosis is challenging as the disease can be associated with or misdiagnosed as biliary atresia. Patients with ALGS are at high risk of morbidity either by unnecessary intraoperative cholangiogram or unavoidable liver transplantation., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Advanced Biomedical Research.)

Background: Chromosome 5p partial monosomy (5p-syndrome) and chromosome 6p partial trisomy are chromosomal abnormalities that result in a variety of symptoms, but liver dysfunction is not normally one of them. Alagille syndrome (OMIM #118450) is a multisystem disorder that is defined clinically by hepatic bile duct paucity and cholestasis, in association with cardiac, skeletal, and ophthalmologic manifestations, and characteristic facial features. Alagille syndrome is caused by mutations in JAG1 on chromosome 20 or NOTCH2 on chromosome 1. Here, we report a preterm infant with karyotype 46,XX,der(5)t(5,6)(p15.2;p22.3) and hepatic dysfunction, who was diagnosed as having incomplete Alagille syndrome., Case Presentation: The Japanese infant was diagnosed based on the cardiac abnormalities, ocular abnormalities, characteristic facial features, and liver pathological findings. Analysis of the JAG1 and NOTCH sequences failed to detect any mutations in these genes., Conclusions: These results suggest that, besides the genes that are known to be responsible for Alagille syndrome, other genetic mutations also may cause Alagille syndrome., (© 2023. The Author(s).)

Odevixibat is synthesized through chemical modification of Benzothiazepine's structure. It is a tiny chemical that inhibits the ileal bile acid transporter and is used to treat a variety of cholestatic illnesses, including progressive familial intrahepatic cholestasis (PFIC). For cholestatic pruritus and liver disease development, bile acid transporter inhibition is a unique treatment strategy. Odevixibat reduces enteric bile acid reuptake. Oral odevixibat was also studied in children with cholestatic liver disease. Odevixibat received its first approval in the European Union (EU) in July 2021 for the treatment of PFIC in patients aged 6 months, followed by approval in the USA in August 2021 for the treatment of pruritus in PFIC patients aged 3 months. Bile acids in the distal ileum can be reabsorbed by the ileal sodium/bile acid cotransporter, a transport glycoprotein. Odevixibat is a sodium/bile acid co-transporter reversible inhibitor. An average 3 mg once-daily dose of odevixibat for a week resulted in a 56% reduction in the area under the curve of bile acid. A daily dose of 1.5 mg resulted in a 43% decrease in the area under the curve for bile acid. Odevixibat is also being evaluated in many countries for the treatment of other cholestatic illnesses, including Alagille syndrome and biliary atresia. This article reviews the updated information on odevixibat with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, drug-drug interactions, pre-clinical studies, and clinical trials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Aims: Alagille syndrome (AGS) is an autosomal dominant multisystem disorder caused by mutations in the JAG1 and NOTCH2 genes. AGS has been rarely reported in adult patients, mainly because its characteristics in adults are subtle. The study aimed to improve the understanding of adult AGS by a descriptive case series., Methods: Eight adults diagnosed with AGS at our hospital between June 2016 and June 2019 were included in the study. Clinical data, biochemical results, imaging results, liver histopathology, and genetic testing were analyzed., Results: Three female and five male patients with a median age of 24.5 years at the time of diagnosis were included in the analysis. The clinical manifestations were adult-onset (62.5%, 5/8), cholestasis (50%, 4/8), butterfly vertebrae (62.5%, 5/8), systolic murmurs (12.5%, 1/8), typical facies (12.5%, 1/8), posterior embryotoxon, and renal abnormalities (0/8). Genetic sequencing showed that all patients had mutations, with four occurring in the JAG1 gene and four in the NOTCH2 gene. Six were substitution mutations, one was a deletion mutation, and one was a splicing mutation. Five had been previously reported; but the others, one JAG1 mutation and two NOTCH2 mutations were unique and are reported here for the first time., Conclusions: The clinical manifestations highlighted by the current diagnostic criteria for most adults with AGS are atypical. Those who do not meet the criteria but are highly suspicious of having AGS need further evaluation, especially genetic testing., Competing Interests: The authors have no conflict of interests related to this publication., (© 2023 Authors.)

Alagille syndrome is a rare autosomal dominant disorder with variable expression. Liver damage, especially cholestatic, is the most common feature of the syndrome. Transgender patients may suffer from a great distress due to the discrepancy between assigned sex at birth and unaffirmed gender identity. Gender affirmation treatment options for these patients include hormone therapy (HT) to induce secondary sexual characteristics and various surgical procedures. Estrogen-based hormonal treatments have been linked to an increased risk of liver enzyme elevation and disruption of bilirubin metabolism, especially in those with a genetic susceptibility. The case presented here is the first described Alagille syndrome transgender patient to undergo gender affirmation treatment, including (HT) and vulvo-vaginoplasty surgery., Competing Interests: No competing financial interests exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

Background: This study aimed to explore the clinical predictors of Alagille syndrome (ALGS) in children and to provide a basis for early diagnosis., Methods: We retrospectively analyzed the clinical data of 14 children diagnosed with ALGS at the First People's Hospital of Lianyungang City from March 2016 to March 2021 and followed up the children., Results: Among the 14 patients, 9 (64.28%) had cholestasis, 12 (85.71%) had heart malformations, 13 (92.85%) had characteristic facial features, 2 (14.28%) had pruritus, and 2 (14.28%) had a positive family history. Among the 13 patients who were examined by pediatric ophthalmologists, 3 patients had ocular lesions. Among the 13 patients who underwent spine radiography, 2 had typical butterfly vertebrae. Among the 6 patients with hepatic pathology, 2 had intracellular cholestasis, 2 had reduced or no small bile duct in the portal area, 2 had small bile duct hyperplasia with massive fibrous hyperplasia and extensive inflammatory cell infiltration, and 2 underwent biliary tract exploration. Genetic testing of 12 children with ALGS revealed JAG1 gene mutations in 7 cases and NOTCH2 gene mutations in 2 cases. The abovementioned two mutant genes were not detected in any of the 3 cases. Among the 12 followed-up patients, 7 were in stable condition, 5 underwent liver transplantation, and 1 died of severe pneumonia., Conclusion: Cholestatic liver disease, cardiac malformations, and abnormal facial development are predictors of ALGS in children and can be definitively diagnosed by genetic testing., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Li et al.)

Alagille syndrome (ALGS) is a rare, debilitating inheritable disease that is associated with refractory pruritus due to chronic cholestasis. The following systemic review and meta-analysis presents the latest evidence for ileal bile acid transport (IBAT) blockers in AGLS patients in order to improve their efficacy. This study adhered to PRISMA 2020 Statement guidelines. A systematic search of PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane library was conducted from inception until 23 October 2022. A combination of the following keywords was used: Alagille syndrome, therapeutics, treatment, therapy. Meta-analytical outcomes included effect directions of end-line changes in serum bile acids (sBAs), Itch Scale scores (ItchRO), Multidimensional Fatigue Scale scores, pediatric quality of life (QL), alanine aminotransferase (ALT), and total bilirubin. A total of 94 patients across four trials were enrolled and received maralixibat, odevixibat, or a placebo. There was a significant reduction in ItchRO scores by 1.8 points, as well as in sBAs by 75.8 μmol/L. Both the Multidimensional Fatigue Scale and Pediatric QL scale were also improved by 11.4 and 8.3 points, respectively. However, ALT levels were raised by 40 U/L. The efficacy of IBAT inhibitors across current trials was noted. Future trials may focus on the optimization of dosing regimens, considering gastrointestinal side effects and drug-induced ALT elevation in AGLS patients.

Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1 Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non-invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1 Ndr/Ndr mice, using retina as a model. Jag1 Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex-specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non-invasive vascular analysis in patients. Finally, Jag1 Ndr/Ndr mice represent a new model for vascular compromise in ALGS., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Pathogenic variants in JAG1 are known to cause Alagille syndrome (ALGS), a disorder that primarily affects the liver, lung, kidney, and skeleton. Whereas cardiac symptoms are also frequently observed in ALGS, thoracic aortic aneurysms have only been reported sporadically in postmortem autopsies. We here report two families with segregating JAG1 variants that present with isolated aneurysmal disease, as well as the first histological evaluation of aortic aneurysm tissue of a JAG1 variant carrier. Our observations shed more light on the pathomechanisms behind aneurysm formation in JAG1 variant harboring individuals and underline the importance of cardiovascular imaging in the clinical follow-up of such individuals., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Alagille Syndrome (ALGS) is a rare, autosomal dominant inherited disorder that causes abnormalities of liver, eye, heart, skeleton and distinctive facial appearance. ALGS is caused by mutation in one of two genes: JAG1 and NOTCH2. There are some reports of Hearing Loss in patients with ALGS raising the possibility of involvement of both structural components of middle ear and sensorineural components of the inner ear. The present case study was to emphasize audiological perspectives of Alagille Syndrome in a nine year old female child. Audiologists must be well aware of the typical features and clinical perspectives of ALGS and should be an expert in selecting appropriate tests and in interpreting findings., Competing Interests: Conflict of interestThe Authors declare that that they have no conflict of interest., (© Association of Otolaryngologists of India 2021.)

Background: Alagille syndrome (ALGS) is a multisystem disorder with variable clinical penetrance. The genes responsible for this disease are JAGGED1 (JAG1) and NOTCH2. Clinical data of this disease are limited in China. The purpose of this study was to enrich the present data of Chinese children with Alagille syndrome by summarizing the clinical characteristics and genetic variations of these cases. From January 2011 to February 2022, 10 children were diagnosed with ALGS. The organs involved in ALGS were as follows: liver (10, 100%); heart (7, 70%); characteristic facial features (7, 70%); skeleton (4, 40%); brain (1,10%) and kidney (3, 30%). Four patients (40%) were small for gestational age. The main clinical manifestations were cholestasis, heart disease, and facial features. The median total bilirubin, direct bilirubin, and total bile acid levels were 138.75 μmol/L (normal, 3.4-20.5 μmol/L), 107.25 μmol/L (normal, 0-8.6 μmol/L), and 110.65 μmol/L (normal, 0.5-10.0 μmol/L), respectively. The median value of gamma-glutamyltranspeptidase was 223 U/L (normal, 9-64 U/L). Six (60%) children had hypercholesteremia. Eight different JAG1 gene variations and one NOTCH2 gene pathogenic variant in the 10 Chinese ALGS patients were identified., Conclusion: Cholestasis was the most common initial presenting symptom in Chinese ALGS pediatric patients. Pathogenic variants in JAG1 and NOTCH2 are the primary mutations in Chinese children with ALGS, but we had our own unique variant spectrum. ALGS should be considered for cholestasis in infants and young children, especially those with multiorgan abnormalities., (© 2022. The Author(s).)

Background and Aim: Alagille syndrome (ALGS) is a multisystem disorder with variable clinical courses. This study investigated the clinical and genetic features of ALGS patients with different outcomes and analyzed the liver pathology at liver transplantation (LT) compared with that in biliary atresia (BA)., Methods: We report the clinical characteristics, outcomes, and genetic mutations of 25 children with ALGS followed for a median of 7.3 years. Patients were classified into (i) jaundice-free (JF) group (resolving jaundice after 2 years of age); (ii) progressive disease (PD) group (persistent jaundice or progressive cholestasis). In addition, we analyzed the explant liver in 10 ALGS patients compared with 20 age-matched BA patients at the time of LT., Results: Nine patients (36%) in the JF group had a favorable outcome, with longer native liver survival than patients with PD ( n  = 16, P  < 0.001). Fourteen of the PD group patients received LT or died. We identified 18 different JAG1 mutations in 22 patients. Three unrelated probands in the JF group had the same de novo mutation in JAG1 , c.2122-2125delCAGT. Compared with BA children, ALGS patients had lower METAVIR scores in liver pathology, higher serum albumin levels, and lower weight-for-age z -scores when receiving LT., Conclusion: One-third of ALGS patients had JF and a favorable course. Children with ALGS presenting with persistent jaundice beyond 2 years of age should be cautioned for poor prognosis. ALGS patients tend to have a lesser extent of cirrhosis, and more growth problems than BA patients at the time of LT., (© 2022 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)