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

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...

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Autores principales: Procházková, Dagmar, Borská, Romana, Fajkusová, Lenka, Konečná, Petra, Hloušková, Eliška, Pavlovský, Zdeněk, Slabý, Ondřej, Pospíšilová, Šárka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230072/
https://www.ncbi.nlm.nih.gov/pubmed/34071626
http://dx.doi.org/10.3390/diagnostics11060983
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author Procházková, Dagmar
Borská, Romana
Fajkusová, Lenka
Konečná, Petra
Hloušková, Eliška
Pavlovský, Zdeněk
Slabý, Ondřej
Pospíšilová, Šárka
author_facet Procházková, Dagmar
Borská, Romana
Fajkusová, Lenka
Konečná, Petra
Hloušková, Eliška
Pavlovský, Zdeněk
Slabý, Ondřej
Pospíšilová, Šárka
author_sort Procházková, Dagmar
collection PubMed
description 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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spelling pubmed-82300722021-06-26 Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic Procházková, Dagmar Borská, Romana Fajkusová, Lenka Konečná, Petra Hloušková, Eliška Pavlovský, Zdeněk Slabý, Ondřej Pospíšilová, Šárka Diagnostics (Basel) Brief Report 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. MDPI 2021-05-28 /pmc/articles/PMC8230072/ /pubmed/34071626 http://dx.doi.org/10.3390/diagnostics11060983 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Procházková, Dagmar
Borská, Romana
Fajkusová, Lenka
Konečná, Petra
Hloušková, Eliška
Pavlovský, Zdeněk
Slabý, Ondřej
Pospíšilová, Šárka
Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic
title Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic
title_full Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic
title_fullStr Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic
title_full_unstemmed Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic
title_short Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic
title_sort two novel mutations in the jag1 gene in pediatric patients with alagille syndrome: the first case series in czech republic
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230072/
https://www.ncbi.nlm.nih.gov/pubmed/34071626
http://dx.doi.org/10.3390/diagnostics11060983
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