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Cited by 169Cerebrovascular and genetic disordersGenetic Neurodegenerative DiseasesIntracerebral and Subarachnoid Hemorrhage Research

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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

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Rutten, Julie W., Van Eijsden, Bastian J., Duering, Marco, Jouvent, Eric, Opherk, Christian, Pantoni, Leonardo, Federico, Antonio, Dichgans, Martin, Markus, Hugh S., Chabriat, Hugues, Lesnik Oberstein, Saskia A.J.·2019·Genetics in Medicine
DOI 10.1038/s41436-018-0088-3PMC PMC6752295
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Abstract

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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Fig. 1 Mutations in NOTCH3 EGFr domains 1–6 are associated with an earlier age of onset of stroke and lower life expectancy than PV in EGFr domains 7–34. a, b, Kaplan–Meier plots showing the differences in (a) age of onset of first stroke and (b) survival stratified according to mutation position for patients with epidermal growth factor-like repeat (EGFr) domain 1–6 PV versus those with EGFr domain 7–34 PV
Fig. 1 Mutations in NOTCH3 EGFr domains 1–6 are associated with an earlier age of onset of stroke and lower life expectancy than PV in EGFr domains 7–34. a, b, Kaplan–Meier plots showing the differences in (a) age of onset of first stroke and (b) survival stratified according to mutation position for patients with epidermal growth factor-like repeat (EGFr) domain 1–6 PV versus those with EGFr domain 7–34 PVCC BY · PubMed Central
Fig. 2 Mutations in NOTCH3 EGFr domains 1–6 are associated with a higher nWMHV than mutations in EGFr domains 7–34 . Scatterplot showing the correlation between normalized white matter hyperintensity volume (nWMHV) and age, stratified according to epidermal growth factor-like repeat (EGFr) group. Diagnosed CADASIL patients with a mutation in one of EGFr domains 1–6 have a higher nWMHV than patients with a mutation in one of EGFr domains 7–34
Fig. 2 Mutations in NOTCH3 EGFr domains 1–6 are associated with a higher nWMHV than mutations in EGFr domains 7–34 . Scatterplot showing the correlation between normalized white matter hyperintensity volume (nWMHV) and age, stratified according to epidermal growth factor-like repeat (EGFr) group. Diagnosed CADASIL patients with a mutation in one of EGFr domains 1–6 have a higher nWMHV than patients with a mutation in one of EGFr domains 7–34CC BY · PubMed Central
Fig. 3 Location of NOTCH3 mutations between diagnosed CADASIL patients and individuals in the gnomAD database. Pie charts displaying the differences in the number of mutations located in EGFr domains 1–6 versus 7–34, between European CADASIL patients and European individuals with a NOTCH3 mutation in gnomAD
Fig. 3 Location of NOTCH3 mutations between diagnosed CADASIL patients and individuals in the gnomAD database. Pie charts displaying the differences in the number of mutations located in EGFr domains 1–6 versus 7–34, between European CADASIL patients and European individuals with a NOTCH3 mutation in gnomADCC BY · PubMed Central

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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)
DOI
10.1038/s41436-018-0088-3
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
FWCI
8.49
Type
journal article
Language
en
Update notices
erratum (2019-08-01)
Open access
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 › Clinical Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Clinical 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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