Targeted Exonic Sequencing Identifies Novel Causes of Disease in a Cerebral Small Vessel Disease Cohort

Abstract

Cerebral small vessel diseases (CSVDs) are a set of conditions that affect the small blood vessels in the brain and can cause severe neurological pathologies such as stroke and vascular dementia. The most common monogenic CSVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which is caused by mutations in NOTCH3. However, only 15-20% of CADASIL cases referred for genetic testing have pathogenic mutations in NOTCH3. Investigation of other monogenic forms of CSVD caused by HTRA1, COL4A1, COL4A2, CTSA, TREX1 and GLA were rarely requested as follow-up to CADASIL diagnostic testing. We performed whole exome sequencing for 50 individuals suspected of having CADASIL, but did not exhibit a disease-causing mutation in NOTCH3, and applied targeted analysis of all monogenic forms of CSVD including NOTCH3, HTRA1, COL4A1, COL4A2, CTSA, TREX1 and GLA to look for rare, protein-altering mutations. We identified three mutations affecting the Collagen type IV genes in three individuals likely to be causative of CSVD. This suggests that screening for all monogenic forms of CSVD when one monogenic form is clinically suspected may improve diagnosis in clinically suspected monogenic CSVD. However, despite these findings, the majority of NOTCH3 negative CSVD cases did not have candidate mutations in known CSVD genes, suggesting that additional genetic factors contributing to the disease are yet to be identified.

NOTCH3 Variants in Patients with Suspected CADASIL

“…They did not identify the synonym A40A as a pathogenic variant but commented that it may cause CADASIL without altering cysteine residues. [ 15 ] A heterozygous A40A (c.120C>T) variant was detected in a 37-year-old female patient who suffered from migraine attacks with visual impairment and a 46-year-old male patient with a history of hemiplegia due to stroke. Both patients had WMH, but the lesions were more extensive in the male patient.…”