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.

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.

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.

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.

阿拉杰里综合征是儿科胆汁淤积性肝病的重要遗传病因，也是伴有多系统受累的最常见的胆汁淤积症病因。因为相对罕见，且临床表现多变，造成误诊和漏诊相当常见，进而延误治疗。为改进对阿拉杰里综合征相关肝病的管理，中国罕见病联盟遗传性肝病分会等组织了儿科肝病相关专家经过证据筛查和反复讨论共同制订了“阿拉杰里综合征相关肝病诊治共识（2024）”，旨在更好地指导临床实践，帮助儿科医生尽早识别该病，并通过科学管理以改善患儿预后。.

BACKGROUND: Liver transplantation (LTx) constitutes a major life-saving routine treatment for children with end-stage liver disease. However, the analysis of LTx registries in children provides much information about changes in the indication profiles in the recent years.
METHODS: The article provides a comprehensive review about the successes, hopes, and challenges related to changing indications for LTx in children based on the literature review and our own experience. Retrospective review of the indications for LTx at a tertiary referral pediatric hospital was also presented.
CONCLUSIONS: In the context of the new therapies that have emerged, the need for LTx has decreased in patients with chronic hepatitis B and C infection and tyrosinemia type 1. In primary hyperoxaluria type 1, new RNAi-based therapy has eliminated the requirement for LTx (both isolated or combined). There is a hope that introduction of ileal bile acid transporter (IBAT) blockers reduces the need for LTx in patients with Alagille syndrome or progressive familial intrahepatic cholestasis. The number of children qualified for LTx with urea cycle disorders (UCDs) as a prophylaxis of neurodevelopmental impairment is increasing.

UNASSIGNED: To explore patterns of disease expression in Alagille syndrome (ALGS).
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

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.

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.

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.