NOTCH3

Inheritance Pattern: AD

Disease ID:MONDO:0000914

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0000914

Submitter: ClinGen

NOTCH receptor 3 (*NOTCH3*) was first reported in relation to cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy (CADASIL) in 1997 (Joutel et al., PMID 9388399). CADASIL often presents initially with migraines usually with aura and progresses to recurrent cerebral ischemic events, and cognitive decline (PMID 28231783). The disease is most commonly associated with cysteine altering variants (cysteine sparing variants have also been observed) in the epidermal growth factor receptor (EGFr) domain consisting of 34 repeats (exons 2-24) with variable severity based on where in the domain the variant occurs (PMID 41018180). Accumulation of granular osmiophilic material, which consists of the *NOTCH3*-extracellular domain, is considered a hallmark of the disease though there are examples of patients where this finding was absent (PMID 32231578). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in the molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1 (OMIM:125310), Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1 (OMIM:621295), Lateral meningocele syndrome (OMIM:130720), and Lipodystrophy, familial partial, type 1 (OMIM:608600). There are several cases with CADASIL features that carry biallelic *NOTCH3* variants however whether those cases are more severe than monoallelic cases is still a topic of debate so this curation will focus on autosomal dominant inheritance (PMID 32457593). The split curations for Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1 (OMIM:621295), Lateral meningocele syndrome (OMIM:130720), and Lipodystrophy, familial partial, type 1 (OMIM:608600) will be curated separately. To date, over 280 *NOTCH3* variants have been reported in CADASIL cases but this curation will focus on a total of 12 variants (10 missense, and 2 short, in-frame deletions) that have been reported in 12 probands in 12 publications (PMIDs 10716263, 11706120, 11486103, 18273901, 23572112, 25604251, 15304596, 21217157, 16717210, 25959358, 35523050) are included in this curation. Case-control evidence from a cohort of dementia and stroke patients with a well-matched control cohort showed a significant enrichment of rare, EGFr domain variants in the cases vs controls (PMID 34404235). The mechanism of pathogenicity appears to involve aggregates of NOTCH3 extracellular domain in vessel walls but there is also evidence that altered interactions with ligands like JAG1 are part of the mechanism (PMID 32231578). This gene-disease relationship is also supported by animal models, expression data, cell culture models and functional alteration studies (PMIDs 42002114, 38592587, 23715323, 39759869, 41806331, 21217517). Two mouse models are able to recapitulate either the aggregate formation alone or aggregate formation and cognitive decline while the cell culture models provide further evidence of aggregate formation and vessel wall changes. Lastly, functional alteration evidence shows that in some cases there may be a dominant negative effect with aggregate formation and that receptor-ligand interactions can be altered leading to downstream effects on transcriptional regulation. In summary, there is definitive evidence supporting the relationship between *NOTCH3* and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Neurovascular Gene Curation Expert Panel on the meeting date June 24, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0016824

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0000914

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0000914

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0000914

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014122

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0000914

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0100241

Submitter: ClinGen

The relationship between *NOTCH3* and thrombocytopenia is supported by limited evidence. A single case report by Zhao and Li (2019; PMID: 31729093) described a family of Miao ethnicity with thrombocytopenia and a heterozygous *NOTCH3* missense variant R1694Q. The variant segregated with thrombocytopenia in the family, but the pedigree was small and no functional studies were performed. No other thrombocytopenia-associated genes were implicated. Experimental evidence directly linking *NOTCH3* to platelet biology is lacking. Indirect evidence suggests that Notch signaling plays a role in megakaryopoiesis and platelet activation (PMID: 26002683; PMID: 32277177), but these studies involve *NOTCH1* or *NOTCH2* rather than *NOTCH3.* Mouse and zebrafish models of *NOTCH3* loss-of-function show vascular defects and hemorrhage (PMID: 28293466; PMID: 24139282), but no platelet count abnormalities have been reported. Large CADASIL cohorts (PMID: 33712516; PMID: 35862191) and other *NOTCH3*-related phenotypes do not include thrombocytopenia as a feature and do not report the R1694Q variant in cases (MIM#s 615293, 125310, 621295, 130720, 608600 will be curated seperately). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

Inheritance Pattern: AD

Disease ID:MONDO:0007537

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

After a comprehensive literature review, the gene-disease relationship between NOTCH3 and pulmonary arterial hypertension is disputed. Despite experimental evidence including function in biochemical pathways, functional alteration in non-human cells, and expression data suggesting a role for NOTCH3 in pulmonary arterial hypertension, there is no genetic evidence to support a classification of limited. Instead, a classification of disputed was reached due to insufficient proband level evidence over multiple years. Classification approved by Pulmonary Hypertension GCEP panel on 8/30/2022 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0007537

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0979867

Submitter: ClinGen

Notch Receptor 3 (*NOTCH3*) was first reported in relation to cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1 in 2015 (Pipucci et al., PMID 25870235). Biallelic null variation in *NOTCH3* is associated with, but not limited to the following features: early onset leukoencephalopathy, seizure, early onset stroke, global developmental delay and spasticity. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanism and inheritance pattern. Therefore, the following disease entities have been split into two disease entities, Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1 (OMIM: 125310), Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1 (OMIM: 621295). Myofibromatosis, infantile 2 (OMIM: 615293), Lateral meningocele syndrome (OMIM: 130720), and Lipodystrophy, familial partial, type 1 (OMIM: 608600) which have also been associated with *NOTCH3* variation are not curated here as they represent different disease entities characterized by specific variant localization or a lack of case data to clearly determine their relationship with the current curation. The split curation for Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1 (OMIM: 125310) has been curated separately. 8 variants (1 missense, 2 nonsense, and 5 frameshift) that have been reported in 7 probands in 6 publications (PMIDs: 25870235, 35026854, 38824264, 37688971, 32980981, 41196431) are included in this curation. The mechanism of pathogenicity appears to be loss of function (PMID 39191170). This gene-disease relationship is also supported by mouse model and expression data (PMIDs 23715323, 18347334, 25477343). Knock-out mouse models show a more severe reaction to induced ischemic injury than WT mice, an effect which was rescued by WT human *NOTCH3*; and damage to vascular smooth muscle tissue similar to that found in patients. Additionally, *NOTCH3* is heavily expressed in vascular tissue which is relevant to the disease features in cases. In summary, there is definitive evidence supporting the relationship between *NOTCH3* and autosomal recessive *NOTCH3*-related autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Neurovascular GCEP on the meeting date August 26, 2026 (SOP Version 12).