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

Abstract

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.

Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease

“…The fact that our MCs did not consistently show activation of NOTCH3 signaling during the repeatability experiments as reported in the previous study using iPSC from a single patient emphasizes the importance of sufficient sample size and repeated experiments [26]. It is not unlikely that such variations in responses within MCs exist in situ explaining the known wide pathogenic variants of the CADASIL phenotype [40]. Future studies are recommended to include at least 4 cases per group or use control iPSC lines transfected with CADASIL-mutation to minimize the effects of genetic background.…”

Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

“…With a prevalence of mutation carriers estimated between 0.8 to 5 per 100,000 individuals, CADASIL is considered, according to the European definition for rare disease (a disease affecting less than 1 person per 2,000), a rare disease (Razvi et al, 2005;Chabriat et al, 2009;Narayan et al, 2012;Moreton et al, 2014). However, recent data suggest a higher prevalence of NOTCH3 pathogenic variants in the general population worldwide, with the highest frequency in Asiatic descendant, suggesting that CADASIL may manifest with milder clinical variants that currently remain undiagnosed (Rutten et al, 2016;Rutten et al, 2019). Accordingly, an extensive retrospective Italian study found a minimum prevalence of CADASIL of 4.1 per 100.000 adult inhabitants, significantly higher compared to that observed in two previous epidemiologic studies conducted in the northeast England and west of Scotland which reported a prevalence of 1.3 and 1.9 per 100.000, respectively (Razvi et al, 2005;Narayan et al, 2012;Bianchi et al, 2015).…”

“…To date, more than 200 pathogenic variants have been described in CADASIL patients worldwide, all of them involving cysteine residues. Genetic variants not involving cysteine have also been described, but their pathogenic role in disease occurrence remains uncertain (Rutten et al, 2014;Rutten et al, 2019). Rutten et al found a genotype-phenotype correlation depending on mutation position along the 34 EGFR domains.…”

Notch3 in Development, Health and Disease

“…Most CADASIL mutations either substitute or introduce a cysteine within Notch3 EGF modules, potentially destabilising the disulphide bonding pattern and module fold [74]. While CADASIL is reported to affect about 4/100000 of the population, genomic studies have revealed that about 1/300 individuals carry archetypal CADASIL mutations [84,85] and it is possible that the condition is considerably underdiagnosed or has a wider spectrum of severity than previously appreciated. Supporting the latter, the distribution of mutations in the general population differs from that of diagnosed CADASIL cases.…”

“…Supporting the latter, the distribution of mutations in the general population differs from that of diagnosed CADASIL cases. From studies of diagnosed CADASIL cases, it has been found that there is a pronounced clustering of disease-associated mutations in the five N-terminal EGF modules, while population genomics studies show less clustering in the N-terminal region [84,85]. A comparison of clinical data suggested that CADASIL mutations affecting the N-terminal region tended to have more severe outcomes and earlier disease onset.…”