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 <i>JAG1</i> or <i>NOTCH2</i> gene. The vari...
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| author | Natalia Semenova Elena Kamenets Eleonora Annenkova Andrey Marakhonov Elena Gusarova Nina Demina Daria Guseva Inga Anisimova Anna Degtyareva Natalia Taran Tatiana Strokova Ekaterina Zakharova |
| author_facet | Natalia Semenova Elena Kamenets Eleonora Annenkova Andrey Marakhonov Elena Gusarova Nina Demina Daria Guseva Inga Anisimova Anna Degtyareva Natalia Taran Tatiana Strokova Ekaterina Zakharova |
| author_sort | Natalia Semenova |
| collection | DOAJ |
| 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 <i>JAG1</i> or <i>NOTCH2</i> 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 <i>JAG1</i> and <i>NOTCH2</i> 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 <i>JAG1</i> 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 <i>NOTCH2</i> 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. |
| first_indexed | 2024-03-11T00:59:31Z |
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| language | English |
| last_indexed | 2024-03-11T00:59:31Z |
| publishDate | 2023-07-01 |
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| spelling | doaj.art-4321120b3b9a44b48123ce5b343cd07d2023-11-18T19:44:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124141175810.3390/ijms241411758Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver DiseaseNatalia Semenova0Elena Kamenets1Eleonora Annenkova2Andrey Marakhonov3Elena Gusarova4Nina Demina5Daria Guseva6Inga Anisimova7Anna Degtyareva8Natalia Taran9Tatiana Strokova10Ekaterina Zakharova11Research Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaNational Medical Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov, Ministry of Health of the Russian Federation, 115522 Moscow, RussiaFederal Research Centre of Nutrition and Biotechnology, 115522 Moscow, RussiaFederal Research Centre of Nutrition and Biotechnology, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaAlagille 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 <i>JAG1</i> or <i>NOTCH2</i> 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 <i>JAG1</i> and <i>NOTCH2</i> 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 <i>JAG1</i> 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 <i>NOTCH2</i> 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.https://www.mdpi.com/1422-0067/24/14/11758Alagille syndromecholestasisbiochemical characteristics<i>JAG1</i> gene |
| spellingShingle | Natalia Semenova Elena Kamenets Eleonora Annenkova Andrey Marakhonov Elena Gusarova Nina Demina Daria Guseva Inga Anisimova Anna Degtyareva Natalia Taran Tatiana Strokova Ekaterina Zakharova Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease International Journal of Molecular Sciences Alagille syndrome cholestasis biochemical characteristics <i>JAG1</i> gene |
| 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 | Alagille syndrome cholestasis biochemical characteristics <i>JAG1</i> gene |
| url | https://www.mdpi.com/1422-0067/24/14/11758 |
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