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02 September 2022 : Case report  Saudi Arabia

[In Press] Pathogenic Novel Heterozygous Variant c.1076c>T p. (Ser359Phe) chr1: 120512166 in NOTCH2 Gene, Type 2 Alagille Syndrome Causing Neonatal Cholestasis: A Case Report

Unusual clinical course, Challenging differential diagnosis, Rare disease, Congenital defects / diseases

Mohammed Shahab Uddin ORCID logo1ACDEF, Saleh Al Fulayyih ORCID logo1BDE, Fatin Fahad Al Denaini ORCID logo1BFG, Maher Mohammed Al Hatlani1ADEF

DOI: 10.12659/AJCR.935840

Am J Case Rep In Press; DOI: 10.12659/AJCR.935840  

Available online: 2022-09-02, In Press, Corrected Proof

Publication in the "In-Press" formula aims at speeding up the public availability of the pending manuscript while waiting for the final publication. The assigned DOI number is active and citable. The availability of the article in the Medline, PubMed and PMC databases as well as Web of Science will be obtained after the final publication according to the journal schedule


Alagille syndrome (ALGS) is a multisystem hereditary illness with a dominant pattern and partial penetrance. Multiple organ abnormalities can be caused by mutations in the Jagged canonical Notch ligand 1 (JAG1) gene. Notch receptor 2 (NOTCH2) gene mutations are also uncommon. ALGS is also characterized by deformed or narrowed bile ducts and is notoriously difficult to diagnose due to the wide range of symptoms and absence of unambiguous genotype-phenotype connections. Little is known about ALGS patients who have NOTCH2 mutations. We present a patient who developed progressive liver failure due to a unique pathogenic heterozygous variation of the NOTCH2 gene, c.1076c>T p. (Ser359Phe) chr1: 120512166, resulting in type 2 ALGS.
A Saudi Arabian newborn with bilateral hazy eyes, ectropion, dry ichthyic skin, normal male genitalia, and bilateral undescended testes was born at 31 weeks. Previous miscarriages, pregnancy-induced maternal cholestasis, fatty liver, or neonatal jaundice were not reported in the family history. He had developed worsening cholestatic jaundice by the third week of hospitalization. The extensive work-up for metabolic, infectious, and other relevant etiologies was negative. Following gram-negative sepsis, he died of multiorgan failure. A NOTCH2 gene mutation explained the phenotypic difference in our situation. Another intriguing observation was the presence of ichthysis and craniosynostosis in ALGS with a NOTCH2 mutation.
Cholestasis in newborns can be difficult to diagnose. Next-generation sequencing detects 112 copy number variants in the cholestasis gene panel blood test. More research is needed to understand why NOTCH2 mutations are relatively rare in ALGS.

Keywords: Alagille Syndrome; Cholestasis; Cholestasis, Intrahepatic; Craniosynostoses; High-Throughput Nucleotide Sequencing; Whole Exome Sequencing; Whole Genome Sequencing; JAG1 Protein, Human


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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923