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.
Rutten, Julie W
Van Eijsden, Bastian J
Markus, Hugh S
Lesnik Oberstein, Saskia AJ
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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
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.
Brain, Humans, CADASIL, Disease Progression, Phenotype, Adult, Aged, Middle Aged, Netherlands, Female, Male, Stroke, Receptor, Notch3, Protein Domains
External DOI: https://doi.org/10.1038/s41436-018-0088-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284713
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/