Clinical and neuroradiological spectrum of biallelic variants in NOTCH3

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Abstract: Background
NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised.
Methods
In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants.
Findings
Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches.
Interpretation
We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: EBioMedicine. - 107 (2024) , 105297, ISSN: 2352-3964

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2024

Creator: Iruzubieta, Pablo
Alves, César Augusto Pinheiro Ferreira
Al Shamsi, Aisha M.
Schmidts, Miriam
Maroofian, Reza

DOI: 10.1016/j.ebiom.2024.105297

URN: urn:nbn:de:bsz:25-freidok-2567729

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 15.08.2025, 7:30 AM CEST

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Associated

Iruzubieta, Pablo
Alves, César Augusto Pinheiro Ferreira
Al Shamsi, Aisha M.
Schmidts, Miriam
Maroofian, Reza
Universität

Time of origin

2024

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Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy

Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy

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Clinical and neuroradiological spectrum of biallelic variants in NOTCH3

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Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy

Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy

The many faces of congenital anomalies of the kidney and urinary tract

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

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TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

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