Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy

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.

NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review

“…We then performed an analysis of mitochondrial DNA and mitochondrial-associated genes without obtaining significant results. The re-examination of exome sequencing data following the publication of Helman et al [ 4 ] allowed us to reach a diagnosis through the identification of a c.4788_4799dup NOTCH1 -variant in our proband. This novel variant is a frameshift insertion located in extracellular negative regulatory region (NRR)-domain as in the series published by Helman et al [ 4 ].…”

“…The re-examination of exome sequencing data following the publication of Helman et al [ 4 ] allowed us to reach a diagnosis through the identification of a c.4788_4799dup NOTCH1 -variant in our proband. This novel variant is a frameshift insertion located in extracellular negative regulatory region (NRR)-domain as in the series published by Helman et al [ 4 ]. This variant is absent in gnomAD ( , accessed on 1 March 2023) and other public databases and was not detected in the child’s healthy mother and brother.…”

“…We found only two papers describing this new entity. Helman and colleagues [ 4 ] described a case-series of seven patients, followed by a case report by Nicita and colleagues [ 15 ]. To date, we know that disease onset is variable, with 66% of cases manifesting in infancy (during the first year of life) and 33% at a later age, ranging from 6 to 40 years.…”

“…Germline heterozygous loss-of-function variants in NOTCH1 are associated with Adams–Oliver syndrome (OMIM 90198) [ 1 ] and aortic valve disease 1 [ 2 ] (OMIM 109730), while somatic variants are implicated in carcinogenesis [ 3 ]. Recently, Helman and colleagues [ 4 ] described NOCHT1 heterozygous gain-of-function variants to cause a new entity that neuroradiologically resembles the inflammatory microangiopathy seen in type I interferonopathies such as Aicardi–Goutières syndrome (AGS). In a series of seven cases, they described shared features of leukoencephalopathy, microangiopathy and calcifications, involvement of both the central and peripheral nervous system and elevated levels of the CXCL10 chemokine (also called IP-10) in the cerebrospinal fluid (CSF).…”

“…In a series of seven cases, they described shared features of leukoencephalopathy, microangiopathy and calcifications, involvement of both the central and peripheral nervous system and elevated levels of the CXCL10 chemokine (also called IP-10) in the cerebrospinal fluid (CSF). In contrast to the majority of cases of AGS, evidence of enhanced interferon signalling in blood was not observed [ 4 ].…”