Systematic Review of Cerebral Phenotypes Associated with Monogenic Cerebral Small Vessel Disease

Ed Whittaker, Sophie Trippleton, Liza Y W Chong, Victoria G Collins, Amy C Ferguson, David E Henshall , Emily Lancastle, Tim Wilkinson, Blair Wilson, Kirsty Wilson, Cathie L M Sudlow, Joanna M. Wardlaw, Kristiina Rannikmae

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Cerebral small vessel disease (cSVD) is an important cause of stroke and vascular dementia. Most cases are multifactorial, but an emerging minority have a monogenic cause.

While NOTCH3 is the best-known gene, several others have been reported. We aimed to summarise the cerebral phenotypes associated with these more recent cSVD genes.

Methods and Results:
We performed a systematic review (PROSPERO: RD42020196720), searching Medline/Embase (conception to July 2020) for any language publications describing COL4A1/2, TREX1, HTRA1, ADA2, or CTSA pathogenic variant carriers. We extracted data about individuals’ characteristics, clinical and vascular radiological cerebral phenotypes. We summarised phenotype frequencies per gene, comparing patterns across genes.

We screened 6,485 publications including 402, and extracted data on 390 COL4A1, 123 TREX1, 44 HTRA1 homozygous, 41 COL4A2, 346 ADA2, 82 HTRA1 heterozygous, and 14 CTSA individuals. Mean age ranged from 15 (ADA2) to 59 years (HTRA1 heterozygotes).

Clinical phenotype frequencies varied widely: stroke 9% (TREX1) to 52% (HTRA1
heterozygotes), cognitive features 0% (ADA2) to 64% (HTRA1 homozygotes), psychiatric features 0% (COL4A2; ADA2) to 57% (CTSA). Among individuals with neuroimaging, vascular radiological phenotypes appeared common, ranging from 62% (ADA2) to 100% (HTRA1 homozygotes; CTSA). White matter lesions were the most common pathology, except in ADA2 and COL4A2 cases, where ischaemic and haemorrhagic lesions dominated, respectively.

There appear to be differences in cerebral manifestations across cSVD genes.

Vascular radiological changes were more common than clinical neurological phenotypes, and present in the majority of individuals with reported neuroimaging. However, these results may be affected by age and biases inherent to case reports. In the future, better characterisation of associated phenotypes, as well as insights from population-based studies, should improve our 2
JAHA/2022/025629-T /R1 understanding of monogenic cSVD to inform genetic testing, guide clinical management, and help unravel underlying disease mechanisms.
Original languageEnglish
Article numbere025629
JournalJournal of the American Heart Association Cardiovascular and Cerebrovascular Disease
Issue number12
Early online date14 Jun 2022
Publication statusPublished - 21 Jun 2022


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