Association of Very Rare Variants with Clinical Features of Alagille Syndrome

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2024 Aug 29

PMID 39202394

Authors

Martina Ferrandino

Giovanna Cardiero

Fabiola Di Dato

Ylenia Cerrato

Luigi Vitagliano

Claudia Mandato

Filomena Morisco

Maria Immacolata Spagnuolo

Raffaele Iorio

Maria Donata di Taranto

Giuliana Fortunato

Affiliations

Soon will be listed here.

Abstract

Background: Alagille syndrome (ALGS) is a rare autosomal dominant genetic disease caused by pathogenic variants in two genes: Jagged Canonical Notch Ligand 1 () and Notch Receptor 2 (). It is characterized by phenotypic variability and incomplete penetrance with multiorgan clinical signs.

Methods: Using Next Generation Sequencing (NGS), we analyzed a panel of liver-disease-related genes in a population of 230 patients with cholestasis and hepatopathies. For the rare variants, bioinformatics predictions and pathogenicity classification were performed.

Results: We identified eleven rare variants in 10 patients, two variants being present in the same patient. Ten variants had never been described before in the literature. It was possible to classify only two null variants as pathogenic, whereas the most of variants were missense (8 out of 11) and were classified as uncertain significance variants (USVs). Among patients with ALGS suspicion, two carried null variants, two carried variants predicted to be pathogenic by bioinformatics, one carried a synonymous variant and variants in glycosylation-related genes, and two carried variants predicted as benign in the PEST domain.

Conclusions: Our results increased the knowledge about variants and the related phenotype, allowing us to improve the genetic diagnosis of ALGS.

Citing Articles

Clinical and genetic characteristics of patients with Alagille syndrome in China: identification of six novel and mutations.

Chen L, Chen J, Lou J, Yu J Transl Pediatr. 2025; 13(12):2144-2154.

PMID: 39823011 PMC: 11732638. DOI: 10.21037/tp-24-301.

References

Maria Maruotti G, Frisso G, Calcagno G, Fortunato G, Castaldo G, Martinelli P . Prenatal diagnosis of inherited diseases: 20 years' experience of an Italian Regional Reference Centre. Clin Chem Lab Med. 2013; 51(12):2211-7. DOI: 10.1515/cclm-2013-0194. View

Morrissette J, Colliton R, Spinner N . Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. Hum Mol Genet. 2001; 10(4):405-13. DOI: 10.1093/hmg/10.4.405. View

Camastra F, di Taranto M, Staiano A . Statistical and Computational Methods for Genetic Diseases: An Overview. Comput Math Methods Med. 2015; 2015:954598. PMC: 4464008. DOI: 10.1155/2015/954598. View

Emerick K, Rand E, Goldmuntz E, Krantz I, Spinner N, Piccoli D . Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999; 29(3):822-9. DOI: 10.1002/hep.510290331. View

Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman J, Tsujimoto Y . Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development. 1999; 126(15):3415-24. DOI: 10.1242/dev.126.15.3415. View

Mohan P, Lemoine J, Trotter C, Rakova I, Billings P, Peacock S . Clinical experience with non-invasive prenatal screening for single-gene disorders. Ultrasound Obstet Gynecol. 2021; 59(1):33-39. PMC: 9302116. DOI: 10.1002/uog.23756. View

Li J, Wu H, Chen S, Pang J, Wang H, Li X . Clinical and Genetic Characteristics of Alagille Syndrome in Adults. J Clin Transl Hepatol. 2022; 11(1):156-162. PMC: 9647109. DOI: 10.14218/JCTH.2021.00313. View

Li Z, Abuduxikuer K, Wang L, Hao C, Zhang J, Wang M . Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients. Liver Int. 2022; 42(8):1836-1848. DOI: 10.1111/liv.15292. View

McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M . Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development. 2001; 128(4):491-502. DOI: 10.1242/dev.128.4.491. View

10.

Guegan K, Stals K, Day M, Turnpenny P, Ellard S . JAG1 mutations are found in approximately one third of patients presenting with only one or two clinical features of Alagille syndrome. Clin Genet. 2011; 82(1):33-40. DOI: 10.1111/j.1399-0004.2011.01749.x. View

11.

Ryan M, Bales C, Nelson A, Gonzalez D, Underkoffler L, Segalov M . Bile duct proliferation in Jag1/fringe heterozygous mice identifies candidate modifiers of the Alagille syndrome hepatic phenotype. Hepatology. 2008; 48(6):1989-97. DOI: 10.1002/hep.22538. View

12.

Mitchell E, Gilbert M, Loomes K . Alagille Syndrome. Clin Liver Dis. 2018; 22(4):625-641. DOI: 10.1016/j.cld.2018.06.001. View

13.

Gilbert M, Bauer R, Rajagopalan R, Grochowski C, Chao G, McEldrew D . Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019; 40(12):2197-2220. PMC: 6899717. DOI: 10.1002/humu.23879. View

14.

Barretta F, Mirra B, Monda E, Caiazza M, Lombardo B, Tinto N . The Hidden Fragility in the Heart of the Athletes: A Review of Genetic Biomarkers. Int J Mol Sci. 2020; 21(18). PMC: 7555257. DOI: 10.3390/ijms21186682. View

15.

Jung C, Driancourt C, Baussan C, Zater M, Hadchouel M, Meunier-Rotival M . Prenatal molecular diagnosis of inherited cholestatic diseases. J Pediatr Gastroenterol Nutr. 2007; 44(4):453-8. DOI: 10.1097/MPG.0b013e318036a569. View

16.

Zhou B, Lin W, Long Y, Yang Y, Zhang H, Wu K . Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther. 2022; 7(1):95. PMC: 8948217. DOI: 10.1038/s41392-022-00934-y. View

17.

Alagille D, Odievre M, Gautier M, Dommergues J . Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975; 86(1):63-71. DOI: 10.1016/s0022-3476(75)80706-2. View

18.

Keitel V, Nies A, Brom M, Hummel-Eisenbeiss J, Spring H, Keppler D . A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2). Am J Physiol Gastrointest Liver Physiol. 2002; 284(1):G165-74. DOI: 10.1152/ajpgi.00362.2002. View

19.

di Taranto M, Gelzo M, Giacobbe C, Gentile M, Marotta G, Savastano S . Cerebrotendinous xanthomatosis, a metabolic disease with different neurological signs: two case reports. Metab Brain Dis. 2016; 31(5):1185-8. DOI: 10.1007/s11011-016-9841-y. View

20.

Kamath B, Bauer R, Loomes K, Chao G, Gerfen J, Hutchinson A . NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012; 49(2):138-44. PMC: 3682659. DOI: 10.1136/jmedgenet-2011-100544. View