Functional characterization of 2,832 JAG1 variants supports reclassification for Alagille syndrome and improves guidance for clinical variant interpretation.

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.

Evolution of cerebrovascular imaging and associated clinical findings in children with Alagille syndrome.

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.

Clinical, pathological and genetic characteristics of 17 unrelated children with Alagille Syndrome.

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.

Human Genetics of Tricuspid Atresia and Univentricular Heart.

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.

Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

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.

Human Genetics of Ventricular Septal Defect.

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.

Treatment of Cholestasis in Infants and Young Children.

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.

Findings in percutaneous trans-hepatic cholecysto-cholangiography in neonates and infants presenting with conjugated hyperbilirubinemia: emphasis on differential diagnosis and cholangiographic patterns.

BACKGROUND: Biliary atresia (BA) is one of the causes of conjugated hyperbilirubinemia in infants which if untreated leads to end-stage liver disease and death. Percutaneous Trans-hepatic Cholecysto-Cholangiography (PTCC) is a minimally invasive study which can be utilized in the diagnostic work-up of these patients. This study's purpose is to describe the experience with PTCC in neonates, the imaging findings encountered, and the abnormal patterns which warrant further investigation. METHODS: A 16-year single-center retrospective study of patients with persistent neonatal cholestasis (suspected BA) undergoing PTCC. Patient demographics, laboratory values, PTCC images, pathology and surgical reports were reviewed. RESULTS: 73 patients underwent PTCC (68% male, mean age 8.7 weeks, mean weight 4.0 Kg). The majority of studies were normal (55%). Abnormal patterns were identified in 33 cases, 79% were diagnosed with BA and 12% with Alagille syndrome. Non-opacification of the common hepatic duct with a narrowed common bile duct (42%) and isolated small gallbladder (38%) were the most common patterns in BA. CONCLUSION: PTCC is a minimally invasive study in the diagnostic work-up of infants presenting with conjugated hyperbilirubinemia (suspected BA). Further invasive investigations or surgery can be avoided when results are normal.

Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease.

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_1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168_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.

[Analysis of the serum bile acid profile to facilitate diagnosis and differential diagnosis of NA(+)-taurocholate cotransporting polypeptide deficiency].

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.

Isolated aneurysmal disease as an underestimated finding in individuals with JAG1 pathogenic variants.

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.

Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed. METHODS: Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2. RESULTS: Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ-glutamyltransferase (GGT) (p = .041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p = .038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in-silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p = .003). Comparing this to patients with likely benign (LB) variants, the patients with likely-pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p = .0001). Significantly more patients with LP variants had extra-hepatic phenotypes of ALGS compared with those patients with LB variants (p = .0004). CONCLUSION: When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in-silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.

Clinical and genetic analysis in Chinese children with Alagille syndrome.

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.

Alagille Syndrome and Repeat Oxygenator Failure during Cardiopulmonary Bypass: A Word of Caution.

Alagille syndrome is an autosomal dominant disorder that is caused by heterozygous mutation of JAG1 or NOTCH2 gene that impacts several multisystem organs including but may not be limited to the liver, heart, musculoskeletal, skin, and the eyes. The most common congenital heart defect associated with Alagille syndrome is multilevel right ventricular outflow tract obstruction with multiple central and peripheral branch pulmonary arterial stenoses occurring in up to two-thirds of these patients. We report two cases of Alagille syndrome who underwent extensive pulmonary arterial branch rehabilitation and experienced unusual oxygenator failure during cardiopulmonary bypass (CPB). We present lessons learned from these two cases and the changes that we implemented in our practice that facilitated smooth conduct of CPB in other cases that we performed subsequently.

Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results.

PURPOSE: Detection of all major classes of genomic variants in a single test would decrease cost and increase the efficiency of genomic diagnostics. Genome sequencing (GS) has the potential to provide this level of comprehensive detection. We sought to demonstrate the utility of GS in the molecular diagnosis of 18 patients with clinically defined Alagille syndrome (ALGS), who had a negative or inconclusive result by standard-of-care testing. METHODS: We performed GS on 16 pathogenic variant-negative probands and two probands with inconclusive results (of 406 ALGS probands) and analyzed the data for sequence, copy-number, and structural variants in JAG1 and NOTCH2. RESULTS: GS identified four novel pathogenic alterations including a copy-neutral inversion, a partial deletion, and a promoter variant in JAG1, and a partial NOTCH2 deletion, for an additional diagnostic yield of 0.9%. Furthermore, GS resolved two complex rearrangements, resulting in identification of a pathogenic variant in 97.5% (n = 396/406) of patients after GS. CONCLUSION: GS provided an increased diagnostic yield for individuals with clinically defined ALGS who had prior negative or incomplete genetic testing by other methods. Our results show that GS can detect all major classes of variants and has potential to become a single first-tier diagnostic test for Mendelian disorders.

Pseudotumor cerebri syndrome in a child with Alagille syndrome: intracranial pressure dynamics and treatment outcome after ventriculoperitoneal shunting.

Alagille syndrome (AS) is a rare multisystem disease of the liver, heart, eyes, face, skeleton, kidneys, and vascular system. The occurrence of pseudotumor cerebri syndrome (PTCS) in patients with AS has been reported only exceptionally. Owning to its rarity and a mostly atypical presentation, the diagnosis and natural history of affected patients remain uncertain. We report an atypical case of PTCS in a 4-year-old boy with a known history of AS who presented with bilateral papilledema (PE) on a routine ophthalmological examination. Visual findings deteriorated after treatment with acetazolamide. Continuous intracranial pressure (ICP) monitoring was then utilized to investigate ICP dynamics. Successful treatment with resolution of PE was achieved after ventriculoperitoneal shunting but relapsed due to growth-related dislocation of the ventricular catheter. This report brings new insights into the ICP dynamics and the resulting treatment in this possibly underdiagnosed subgroup of PTCS patients. It also demonstrates that ventriculoperitoneal shunting can provide long-term improvement of symptoms for more than 10 years.

Atrial septal defect occlusion by a catheter during reperfusion of homograft in a case of living donor liver transplantation.

Liver transplantation for patients with atrial septal defect and pulmonary artery stenosis, causing high right atrium pressure, raises concerns about embolism in systemic vessels during reperfusion of the donor liver graft. Temporal atrial septal defect occlusion by a catheter is a simple and easy method of preventing the complication.

The morphological and histopathological assessment of Alagille syndrome with extrahepatic bile duct obstruction: the importance of the differential diagnosis with subgroup "o" biliary atresia.

PURPOSE: The differential diagnosis between Alagille syndrome (AGS) with extrahepatic bile duct obstruction (EHBDO) and biliary atresia (BA) is difficult. We report a case series of AGS with EHBDO with detailed validation of the morphological and histopathological features for the differential diagnosis of BA. METHODS: Six liver transplantations (LTs) were performed for AGS with EHBDO. All patients were diagnosed with BA at the referring institution and the diagnosis of AGS was then confirmed based on a genetic analysis before LT. We verified the morphological and histopathological findings of the porta hepatis and liver at the diagnosis of BA and at LT. RESULTS: All patients had acholic stool in the neonatal period and were diagnosed with BA by cholangiography. The gross liver findings included a smooth and soft surface, without any cirrhosis. The gross findings of the porta hepatis included aplasia of the proximal hepatic duct, or subgroup "o", in five patients. The histopathological examination of the EHBD also revealed obstruction/absence of the hepatic duct. There were no patients with aplasia of the common bile duct. CONCLUSIONS: Aplasia of the hepatic duct and the macroscopic liver findings may help in to differentiate between AGS with EHBDO and BA.

Central Hepatic Regenerative Nodules in Alagille Syndrome: A Clinicopathological Review.

OBJECTIVE: This review aims to highlight the clinicopathological characteristics and differential diagnosis of central hepatic regenerative nodules (CHRNs) in patients with Alagille syndrome. METHODS: A review of the literature for cases of CHRNs and their differential diagnoses in patients with Alagille syndrome was performed and the main findings were collated. RESULTS: Large, regenerative hepatic nodules are seen in approximately 30% of patients with Alagille syndrome. They are thought to be a functional adaptation to vascular changes rather than a neoplastic process. The nodules are typically centrally located, and normal hepatic vasculature coursing through the lesions are noted radiologically. Microscopically, they are characterized by well-circumscribed hepatic lesions with preserved architecture, lesser degrees of fibrosis and relative preservation of interlobular bile ducts compared to the background cirrhotic liver. CONCLUSION: Regenerative nodules are common in Alagille's syndrome, and should be distinguished from hepatocellular carcinomas and adenomas for appropriate management and prognostication.

Peritoneal dialysis in an adult patient with tetralogy of Fallot diagnosed with incomplete Alagille syndrome.

BACKGROUND: Alagille syndrome is an autosomal dominant disorder usually caused by pathogenic variants of the JAG1 gene. In the past, cholestasis was a condition sine qua non for diagnosis of the syndrome. However, recent advancements in genetic testing have revealed that clinical presentations vary from lack of symptoms, to multiorgan involvement. Tetralogy of Fallot, the most frequent complex congenital heart defect in Alagille Syndrome, very rarely leads to renal failure requiring dialysis - there are only single reports of such cases in the literature, with none of them in Alagille Syndrome. CASE PRESENTATION: A 41-year-old woman suffering from cyanosis, dyspnea and plethora was admitted to the hospital. The patient suffered from chronic kidney disease and tetralogy of Fallot and had been treated palliatively with Blalock-Taussig shunts in the past; at admission, only minimal flow through the left shunt was preserved. These symptoms, together with impaired mental status and dysmorphic facial features, led to extensive clinical and genetic testing including whole exome sequencing. A previously unknown missense variant c.587G > A within the JAG1 gene was identified. As there were no signs of cholestasis, and subclinical liver involvement was only suggested by elevated alkaline phosphatase levels, the patient was diagnosed with incomplete Alagille Syndrome. End-stage renal disease required introduction of renal replacement therapy. Continuous ambulatory peritoneal dialysis was chosen and the patient's quality of life significantly increased. However, after refusal of further treatment, the patient died at the age of 45. CONCLUSIONS: Tetralogy of Fallot should always urge clinicians to evaluate for Alagille Syndrome and offer patients early nephrological care. Although tetralogy of Fallot rarely leads to end-stage renal disease requiring dialysis, if treated palliatively and combined with renal dysplasia (typical of Alagille Syndrome), it can result in severe renal failure as in the presented case. There is no standard treatment for such cases, but based on our experience, peritoneal dialysis is worth consideration. Finally, clinical criteria for the diagnosis of Alagille Syndrome require revision. Previously, diagnosis was based on cholestasis - however, cardiovascular anomalies are found to be more prevalent. Furthermore, the criteria do not include renal impairment, which is also common.