SARS-CoV-2 infection activating a novel variant of the NOTCH3 gene and subsequently causing development of CADASIL

Area of Science:

• Genetics
• Neurology
• Infectious Diseases

Background:

• Cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL) is a rare genetic disorder.
• COVID-19, caused by SARS-CoV-2, can present with diverse neurological complications.

Purpose of the Study:

• To investigate the diagnostic process and genetic underpinnings of a patient presenting with both COVID-19 and CADASIL-like symptoms.
• To identify potential links between SARS-CoV-2 infection and the development or exacerbation of CADASIL.

Main Methods:

• Standard diagnostic procedures for COVID-19.
• Whole genome sequencing (WGS) to analyze the patient's and relatives' genetic makeup.
• Identification and characterization of novel gene variants.

Main Results:

• A novel variant in the NOTCH3 gene was identified in the patient, associated with CADASIL-like symptoms.
• This NOTCH3 variant was absent in the patient's close relatives, suggesting a de novo origin.
• The novel NOTCH3 variant is hypothesized to have been activated by SARS-CoV-2 infection.

Conclusions:

• The SARS-CoV-2 infection likely accelerated the development of CADASIL symptoms in this patient.
• The identified de novo NOTCH3 variant may have contributed to a more severe course of COVID-19.
• This case highlights a potential interplay between viral infections and genetic predispositions for neurodegenerative diseases.