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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Authors
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 AJ
Publication Date
2019-03Journal Title
Genet Med
ISSN
1098-3600
Publisher
Elsevier BV
Volume
21
Issue
3
Pages
676-682
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Rutten, J. W., Van Eijsden, B. J., Duering, M., Jouvent, E., Opherk, C., Pantoni, L., Federico, A., et al. (2019). 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.. Genet Med, 21 (3), 676-682. https://doi.org/10.1038/s41436-018-0088-3
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.
Keywords
Brain, Humans, CADASIL, Disease Progression, Phenotype, Adult, Aged, Middle Aged, Netherlands, Female, Male, Stroke, Receptor, Notch3, Protein Domains
Identifiers
External DOI: https://doi.org/10.1038/s41436-018-0088-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284713
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