Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy

Ann Neurol. 2022 Nov;92(5):895-901. doi: 10.1002/ana.26477. Epub 2022 Aug 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Central Nervous System / metabolism
  • Chemokine CXCL10
  • Ectodermal Dysplasia*
  • Humans
  • Leukoencephalopathies*
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism


  • Receptor, Notch1
  • Chemokine CXCL10
  • NOTCH1 protein, human