Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.
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Iruzubieta Pablo, Alves César Augusto Pinheiro Ferreira, Al Shamsi Aisha M, ElGhazali Gehad, Zaki Maha S, Pinelli Lorenzo, Lopergolo Diego, Cho Bernard P H, Jolly Amy A, Al Futaisi Amna, Al-Amrani Fatema, Galli Jessica, Fazzi Elisa, Vulin Katarina, Barajas-Olmos Francisco, Hengel Holger, Aljamal Bayan Mohammed, Nasr Vahideh, Assarzadegan Farhad, Ragno Michele, Trojano Luigi, Ojeda Naomi Meave, Çakar Arman, Bianchi Silvia, Pescini Francesca, Poggesi Anna, Al Tenalji Amal, Aziz Majid, Mohammad Rahema, Chedrawi Aziza, De Stefano Nicola, Zifarelli Giovanni, Schöls Ludger, Haack Tobias B, Rebelo Adriana, Zuchner Stephan, Koc Filiz, Griffiths Lyn R, Orozco Lorena, Helmes Karla García, Babaei Meisam, Bauer Peter, Chan Jeong Won, Karimiani Ehsan Ghayoor, Schmidts Miriam, Gleeson Joseph G, Chung Wendy K, Alkuraya Fowzan Sami, Shalbafan Bita, Markus Hugh S, Houlden Henry, Maroofian Reza
Аннотация
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.
FUNDING: The Wellcome Trust, the MRC.