The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant
Open accessAbstract
PURPOSE: CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7-34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7-34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. METHODS: Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1-6 pathogenic variant or an EGFr 7-34 pathogenic variant. The frequencies of NOTCH3 EGFr 1-6 and EGFr 7-34 pathogenic variant were compared between individuals in the genome Aggregation Database and CADASIL patients. RESULTS: CADASIL patients with an EGFr 1-6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7-34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1-6 pathogenic variant, whereas EGFr 7-34 pathogenic variant strongly predominate in the population. CONCLUSION: NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7-34 pathogenic variant predisposing to a later onset of stroke and longer survival.
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All 4 treated patients who underwent genetic analysis had NOTCH3 variants located outside the classic high-risk EGFr 1-6 domains.
“In addition, all 4 had NOTCH3 variants located outside the classic high-risk EGFr 1–6 domains.14”
From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [14]
The Discussion (page not provided) identifies EGFr 1–6 variants as associated with a more severe CADASIL phenotype than EGFr 7–34 variants, supporting the description of EGFr 1–6 as higher risk. The paper does not identify the four treated patients or report their genetic-analysis results, so it does not support the claim that all four had variants outside those domains. (LLM, conf=0.86)
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- Authors
- Rutten, J. W., Van Eijsden, B. J., Duering, M., Jouvent, E., Opherk, C., Pantoni, L., Federico, A., Dichgans, M., Markus, H. S., Chabriat, H., & Lesnik Oberstein, S. A. J.
- Affiliations
- Leiden University Medical Center (NL)
- LMU Klinikum (DE)
- SLK-Kliniken Heilbronn (DE)
- University of Milan (IT)
- University of Siena (IT)
- University of Cambridge (GB)
- Assistance Publique – Hôpitaux de Paris (FR)
- Corresponding author
- Rutten, Julie W.
- ORCID
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 21
- Issue
- 3
- Pages
- 676-682
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC6752295
- OpenAlex
- W4249518051
- Cited by
- 169
- References
- 17
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 25 · 2023: 18 · 2022: 35 · 2021: 16 · 2020: 23 · 2019: 10 · 2018: 1
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-08-01)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10019, NF-SI-0617-10006)
- Topics
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Keywords
- CADASIL, Notch3, epidermal growth factor-like repeats, disease severity, survival, white matter hyperintensity volume, cerebral small vessel disease
- MeSH terms
- Receptor, Notch3, Protein Domains, Adult, Aged, Brain, Female, Humans, Male, Middle Aged, Netherlands, Phenotype, Disease Progression, Stroke, CADASIL
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