Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome

Ohashi, Kei; Togawa, Takao; Sugiura, Tetsuro; Ito, Koichi; Endo, Takeshi; Aoyama, Kohei; Negishi, Yutaka; Kudo, Takako; Ito, Reiko; Saitoh, Shinji

doi:10.1111/apa.13981

Cited by 9 publications

(10 citation statements)

References 34 publications

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“…Recent studies using JAG1 as a molecular marker of AGS have suggested that in early infancy, AGS-associated BH could mimic BA and genetic testing might help differentiate the two conditions. 37,38 Consistent with a report from Japan, all cases with JAG1 mutations in our study had poor outcome, which suggests that molecular pathology is potentially use-ful in infants with a diagnosis of BA as the data may prognosticate the result of hepatic portoenterostomy or identify those who need early hepatic transplantation. A large series from Japan where targeted sequencing was performed in 109 infants with non-BA cholestasis reported a relatively high incidence of JAG1 mutations (13 cases), and most of these (12/13) had a clinical syndrome compatible with AGS.…”

Section: Discussionsupporting

confidence: 91%

Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand

et al. 2018

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Biliary atresia (BA) is the most severe form of obstructive cholangiopathy occurring in infants. Definitive diagnosis of BA usually relies on operative findings together with supporting pathological patterns found in the extrahepatic bile duct. In infancy, overlapping clinical patterns of cholestasis can be found in other diseases including biliary hypoplasia and progressive familial intrahepatic cholestasis. In addition, BA has been reported as a phenotype in some rare genetic syndromes. Unlike BA, other cholangiopathic phenotypes have their own established genetic markers. In this study, we used these markers to look for other cholestasis entities in cases diagnosed with BA. DNA from 20 cases of BA, diagnosed by operative findings and histopathology, were subjected to a study of 19 genes associated with infantile cholestasis syndromes, using whole exome sequencing. Variant selection focused on those with allele frequencies in dbSNP150 of less than 0.01. All selected variants were verified by polymerase chain reaction-direct sequencing. Of the 20 cases studied, 13 rare variants were detected in 9 genes: 4 in (Alagille syndrome), 2 in (progressive familial intrahepatic cholestasis [PFIC] type 6), and one each in (Dubin-Johnson syndrome), (PFIC type 2), (Crigler-Najjar syndrome), (Kabuki syndrome), (Mitchell-Riley syndrome), (Fanconi anemia), and (Zimmermann-Laband syndrome). Genetic lesions associated with various cholestatic syndromes detected in cases diagnosed with BA raised the hypothesis that severe inflammatory cholangiopathy in BA may not be a distinct disease entity, but a shared pathology among several infantile cholestatic syndromes.

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Section: Discussionsupporting

confidence: 91%

Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand

et al. 2018

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“…Some ALGS1 patients carry the mutation in the JAG1 gene and the diagnosis could not be confirmed on the basis of diagnostic criteria only. Relatives of ALGS patients may show only individual symptoms of the disease, which implies a mild form of the disorder [15,23,24]. In our case, the father of ALGS1 proband no.…”

Section: Discussionmentioning

confidence: 65%

“…Clinical symptoms of ALGS are highly variable both within the same family and among different patients. The high detection rate of mutations in subjects with incomplete ALGS suggests the possibility that a substantial number of patients carrying a JAG1 mutation are not clinically diagnosed with ALGS [23,24]. Examination is crucial for genetic consultancy and for future prenatal and pre-implantation diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic

et al. 2021

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Background: Alagille syndrome (ALGS) is a highly variable multisystem disorder inherited in an autosomal dominant pattern with incomplete penetration. The disorder is caused by mutations in the JAG1 gene, only rarely in the NOTCH2 gene, which gives rise to malformations in multiple organs. Bile duct paucity is the main characteristic feature of the disease. Methods: Molecular-genetic examination of genes JAG1 and NOTCH2 in four probands of Czech origin who complied with the diagnostic criteria of ALGS was performed using targeted next-generation sequencing of genes JAG1 and NOTCH2. Segregation of variants in a family was assessed by Sanger sequencing of parental DNA. Results: Mutations in the JAG1 gene were confirmed in all four probands. We identified two novel mutations: c.3189dupG and c.1913delG. Only in one case, the identified JAG1 mutation was de novo. None of the parents carrying JAG1 pathogenic mutation was diagnosed with ALGS. Conclusion: Diagnosis of the ALGS is complicated due to the absence of clear genotype-phenotype correlations and the extreme phenotypic variability in the patients even within the same family. This fact is of particular importance in connection to genetic counselling and prenatal genetic testing.

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“…This variant was not found in either of the parents. This de novo variant of the JAG1 gene has been reported to be pathogenic in AGS [ 10 , 11 ].…”

Section: Case Reportmentioning

confidence: 99%

A Case of Infantile Alagille Syndrome With Severe Dyslipidemia: New Insight into Lipid Metabolism and Therapeutics

Nakajima

Tsuma

Fukuhara

et al. 2022

Journal of the Endocrine Society

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Alagille syndrome (AGS) is an autosomal dominant genetic disorder characterized by congenital heart disease, hepatic cholestasis, dyslipidemia, and characteristic facies since infancy. Cholestatic hypercholesterolemia in patients diagnosed with AGS is occasionally refractory and resistant to conventional treatments. We report the case of a 4-month-old boy diagnosed with AGS and refractory dyslipidemia due to cholestatic liver disease. He had repeated episodes of cyanosis due to pulmonary artery atresia since birth and underwent a Blalock–Taussig shunt procedure at 3 months of age. At 4 months, cholestatic hyperbilirubinemia deteriorated to a serum total bilirubin level of 19.9 mg/dL. At 12 months, a laboratory test revealed severe dyslipidemia (serum total cholesterol, 1796 mg/dL; serum triglycerides (TG), 635 mg/dl), and the presence of xanthomas. A pathogenic variant of the JAG1 gene (c.1326G>A, p.Trp442X) was detected through genetic testing. Oral ursodeoxycholate normalized hyperbilirubinemia with a subtle improvement in dyslipidemia. Combination therapy with pravastatin and fenofibrate did not successfully improve dyslipidemia. At the age of 20 months, altering pravastatin to atorvastatin was effective in normalizing serum cholesterol and triglycerides with no adverse events. Combination therapy with atorvastatin and fenofibrate was successful in improving refractory dyslipidemia in a child with AGS. Atorvastatin is a well-known strong statin that can lower serum cholesterol, and fenofibrate can lower serum TG levels. We propose that atorvastatin could be taken into consideration for the treatment of persistent hyperlipidemia in patients diagnosed with AGS, because atorvastatin upregulates bile acid synthesis and lipoprotein scavenging, and inhibits intrinsic cholesterol production.

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Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome

Abstract: Combined genetic analyses achieved efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome.

Cited by 9 publications

References 34 publications

Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand

Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand

Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic

A Case of Infantile Alagille Syndrome With Severe Dyslipidemia: New Insight into Lipid Metabolism and Therapeutics

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