Novel mutations in NOTCH2 gene in infants with neonatal cholestasis.

Eliana Shaul,Trang Nguyen,Stephanie Schuckalo,Mercedes Martinez,Dominique Jan,Debora Kogan-Liberman,Nadia Ovchinsky,Michelle Ewart

doi:10.4081/pr.2019.8206

Abstract

One cause of neonatal cholestasis (NC) is paucity of intrahepatic bile ducts which can be associated with Alagille syndrome or non- syndromic. Alagille syndrome is caused by autosomal dominant mutations in the Notch signaling pathway ligand Jagged1 in 94% of patients and mutations in the NOTCH2 receptor in <1% of patients. This is a retrospective case series studying infants with neonatal cholestasis found to have variants of unknown significance (VOUS) in NOTCH2. Sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen) were utilized to predict a damaging effect. Five infants with NC without other features of Alagille syndrome were found to have one copy of a VOUS in NOTCH2, predicted to be damaging by SIFT and PolyPhen. Our cases support the notion that NOTCH2 mutations may result in hypoplastic biliary system. Further characterization of these variants is important to assist with our clinical approach to NC.

Highlights

Introduction one copy of VOUS inNOTCH 2 gene gies of neonatal cholestasis (NC) including infectious, anatomic, (Table 1)
NC is caused by diminished flow and excretion of bile.[1]
PIBD is one cause of NC and is defined by a specimen from a liver biopsy shows a loss of intrahepatic bile ducts in more than 50% of portal tracts in a specimen that contains at least 10 portal tracts.[7]

Summary

Methods

This is a retrospective case series of 5 patients with NC. Data was obtained through a chart review, including electronic medical records, imaging and pathology specimens. PolyPhen-2 predicts the effect of an amino acid substitution on the structure and function of a protein using of data and chart review, technical and administrative support. ©Copyright: the Author(s), 2019 Licensee PAGEPress, Italy Pediatric Reports 2019; 11:8206 doi:10.4081/pr.2019.8206 from tolerant (SIFT) and polymorphism sequence homology, 3D structures where phenotyping (PolyPhen) were utilized to predict a damaging effect. Five infants with NC without other features of Alagille syndrome were found to have one copy of a VOUS in NOTCH2, predicted to be damaging by SIFT and PolyPhen. Our cases support the notion that NOTCH2 mutations may result in hypoplastic biliary system. Further characterization of these variants is important to assist with our clinical approach to NC. NOTCH2 Mutation NOTCH2 VOUS c.5314G>A (p.E1772K) NOTCH2 VOUS c.5314G>A (p.E1772K) NOTCH2 VOUS c.1847G>T (p.C616F) NOTCH2 VOUS c.2102T>A (p.C701E) NOTCH2 VOUS c.4699C>T (p.R1567W)

Not done extrahepatic biliary system

Findings

Discussion