SARS-CoV-2 infection activating a novel variant of NOTCH3 Gene and subsequently causing development of Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL)

IntroductionEncephalopathy and stroke in COVID-19 patients have been repeatedly reported. Previous reports indicate that SARS-CoV-2 infection is associated with a significantly escalated risk of ischemic stroke, especially with potentially cryptogenic stroke. Encephalopathy is also present in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Definitive diagnosis of CADASIL is based on sequencing the NOTCH3 gene. Primary pathology is the accumulation of abnormal transmembrane deposits on vascular smooth muscle cells in the brain and other organs.Material and methodsGenome of the patient was sequenced with the average depth of coverage 32,7x and mapped to the reference genome GRCh38. The whole genome sequencing (WGS) approach identified heterozygous missense variant NOTCH3 in the exon 8. Targeted Sanger sequencing was done to confirm the presence of the variant, and to examine the closest relatives. Beside the patient, all family members were unaffected, the variant appeared de novo.ResultsIdentified variant was not reported in the GnomAD v.3 and 1000 Genomes, nor in polymorphism database dbSNP. No clinical information was available in ClinVar. The only information regarding variants in the same amino acid position (Cs440Ser and Cys440Gly) from LOVD database were reported by Markus et al. They were found in 2 individuals affected with CADASIL and interpreted as pathogenic on the basis of symptoms and familial cosegregation. Beside the patient, all family members were unaffected, the variant appeared de novo.ConclusionsThe simultaneous COVID-19 infection could probably provoke an exacerbation of a previously asymptomatic CADASIL patient and could lead to an acute ischemic multi-infarct encephalopathy.