Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy

Guy Helman, Parand Zarekiani, Samantha A.M. Tromp, Ashley Andrews, Lorenzo D. Botto, Joshua L. Bonkowsky, Anna Chassevent, Elisa Giorgio, Tommaso Pippucci, Shen Wei, Constance Smith-Hicks, Giovanna Vaula, Michèl A.A.P. Willemsen, Mareike Schimmel, Kurt Vollert, Fumitaka Shimizu, Takashi Kanda, Matthew Lynch, Tony Roscioli, Ryan J. TaftCas Simons, Marianna Bugiani, Taco W. Kuijpers, Marjo S. van der Knaap

Research output: Contribution to journalArticlepeer-review

Abstract

NOTCH1 belongs to the NOTCH family of proteins that regulate cell fate and inflammatory responses. Somatic and germline NOTCH1 variants have been implicated in cancer, Adams-Oliver syndrome, and cardiovascular defects. We describe 7 unrelated patients grouped by the presence of leukoencephalopathy with calcifications and heterozygous de novo gain-of-function variants in NOTCH1. Immunologic profiling showed upregulated CSF IP-10, a cytokine secreted downstream of NOTCH1 signaling. Autopsy revealed extensive leukoencephalopathy and microangiopathy with vascular calcifications. This evidence implicates that heterozygous gain-of-function variants in NOTCH1 lead to a chronic central nervous system (CNS) inflammatory response resulting in a calcifying microangiopathy with leukoencephalopathy. ANN NEUROL 2022;92:895–901.

Original languageEnglish (US)
Pages (from-to)895-901
Number of pages7
JournalAnnals of neurology
Volume92
Issue number5
DOIs
StatePublished - Nov 2022

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

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