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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 phen...

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Autores principales: Semenova, Natalia, Kamenets, Elena, Annenkova, Eleonora, Marakhonov, Andrey, Gusarova, Elena, Demina, Nina, Guseva, Daria, Anisimova, Inga, Degtyareva, Anna, Taran, Natalia, Strokova, Tatiana, Zakharova, Ekaterina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380973/
https://www.ncbi.nlm.nih.gov/pubmed/37511516
http://dx.doi.org/10.3390/ijms241411758
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author Semenova, Natalia
Kamenets, Elena
Annenkova, Eleonora
Marakhonov, Andrey
Gusarova, Elena
Demina, Nina
Guseva, Daria
Anisimova, Inga
Degtyareva, Anna
Taran, Natalia
Strokova, Tatiana
Zakharova, Ekaterina
author_facet Semenova, Natalia
Kamenets, Elena
Annenkova, Eleonora
Marakhonov, Andrey
Gusarova, Elena
Demina, Nina
Guseva, Daria
Anisimova, Inga
Degtyareva, Anna
Taran, Natalia
Strokova, Tatiana
Zakharova, Ekaterina
author_sort Semenova, Natalia
collection PubMed
description 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.
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spelling pubmed-103809732023-07-29 Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease Semenova, Natalia Kamenets, Elena Annenkova, Eleonora Marakhonov, Andrey Gusarova, Elena Demina, Nina Guseva, Daria Anisimova, Inga Degtyareva, Anna Taran, Natalia Strokova, Tatiana Zakharova, Ekaterina Int J Mol Sci Communication 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. MDPI 2023-07-21 /pmc/articles/PMC10380973/ /pubmed/37511516 http://dx.doi.org/10.3390/ijms241411758 Text en © 2023 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 Communication
Semenova, Natalia
Kamenets, Elena
Annenkova, Eleonora
Marakhonov, Andrey
Gusarova, Elena
Demina, Nina
Guseva, Daria
Anisimova, Inga
Degtyareva, Anna
Taran, Natalia
Strokova, Tatiana
Zakharova, Ekaterina
Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease
title Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease
title_full Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease
title_fullStr Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease
title_full_unstemmed Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease
title_short Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease
title_sort clinical characterization of alagille syndrome in patients with cholestatic liver disease
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380973/
https://www.ncbi.nlm.nih.gov/pubmed/37511516
http://dx.doi.org/10.3390/ijms241411758
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