| Title: | Small Vessel Disease Phenotype Associated With Monoallelic NOTCH3 Loss-of-Function Variants |
| Journal: | Neurology |
| Published: | 29 Aug 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40882175/ |
| DOI: | https://doi.org/10.1212/wnl.0000000000214021 |
| URL: | https://www.neurology.org/doi/pdf/10.1212/WNL.0000000000214021 |
Publication 19626
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Abstract
BACKGROUND AND OBJECTIVES: Monoallelic cysteine-altering NOTCH3 (NOTCH3cys) variants cause the adult-onset small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and biallelic NOTCH3 loss-of-function (NOTCH3lof) variants cause a rare, childhood-onset small vessel disease. Whether monoallelic NOTCH3lof variants also cause a small vessel disease is subject of debate. The aim of this study was to delineate the small vessel disease phenotype of individuals with a monoallelic NOTCH3lof variant and to compare it with CADASIL.</p>
METHODS: In this observational study, monoallelic NOTCH3lof cases were ascertained in Genome Aggregation Database (gnomAD); UK Biobank; 6 clinical centers from Europe, Asia, and the United States; and literature. In gnomAD, NOTCH3lof allele frequency was determined. In UK Biobank, normalized white matter hyperintensity volume (nWMHv), peak width of skeletonized mean diffusivity (PSMD), lacune count, and stroke were compared among NOTCH3lof cases, NOTCH3cys cases, and controls. In clinical NOTCH3lof cases, white matter hyperintensities, lacune count, and stroke incidence were assessed, and skin vessel wall pathology was analyzed using immunohistochemistry and electron microscopy.</p>
RESULTS: In gnomAD, 306 NOTCH3lof variants were identified (allele frequency 0.6/1,000). In UK Biobank, 102 NOTCH3lof cases were ascertained (median age 58 years, range 40-69, 55% female). NOTCH3lof cases had an increased nWMHv (Δ0.44 mm3, p < 0.001) and PSMD (Δ0.19 × 10-4, p = 0.017) compared with controls. nWMHv and PSMD in NOTCH3lof cases were comparable to NOTCH3cys cases; however, in contrast to NOTCH3cys cases, NOTCH3lof cases did not have an increased stroke risk compared with controls. Clinically ascertained NOTCH3lof cases (n = 69, median age 50 years, range 20-94, 54% female) often had white matter hyperintensities (28/32, 88%) while lacunes (12/32, 38%) and stroke (11/69, 15%) were predominantly seen in cases with cardiovascular risk factors and at advanced age. Skin vessels of NOTCH3lof cases more frequently showed abundant vessel wall collagen deposition compared with NOTCH3cys cases and controls (37% vs 10% [p = 0.016] and 5% [p < 0.001] of vessels).</p>
DISCUSSION: We conclude that monoallelic NOTCH3lof variants cause a small vessel disease that (1) remains subclinical in most cases but may be exacerbated by cardiovascular risk factors and aging, and (2) is distinct from CADASIL regarding vessel pathology and disease severity. These findings will guide counseling and management of individuals in whom a NOTCH3lof variant is found.</p>
11 Keywords
- Adult
- Aged
- CADASIL
- Cerebral Small Vessel Diseases
- Female
- Humans
- Loss of Function Mutation
- Male
- Middle Aged
- Phenotype
- Receptor, Notch3
19 Authors
- Josephine S van Asbeck
- Gido Gravesteijn
- Minne N Cerfontaine
- Jeroen P Vreijling
- Aat A Mulder
- Roman I Koning
- Mark C Kruit
- Anna Bersano
- Keith W Muir
- Sam J Neilson
- James F Meschia
- Md Manjurul Islam Shourav
- Andreas Koupparis
- Yi-Chung Lee
- Nicola Rifino
- Remco J Hack
- Esther A R Nibbeling
- Saskia A J Lesnik Oberstein
- Julie W Rutten
1 Application
| Application ID | Title |
|---|---|
| 74162 | The full phenotypic spectrum of hereditary small vessel diseases and its modifiers |
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