Beyond the Brain: Systematic Review of Extra-Cerebral Phenotypes associated with Monogenic Cerebral Small Vessel Disease

Kristiina Rannikmae, David Henshall, Sophie Thrippleton, Qiu Kong, Michael Chong, Nickrooz Grami, Isaac Kuan, Tim Wilkinson, Blair Wilson, Kirsty Wilson, Guillaume Paré, Cathie L M Sudlow

Research output: Contribution to journalArticlepeer-review


Background and Purpose: An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature.
Methods: We performed a systematic review following the PRISMA guidelines, searching Medline/Embase for publications describing individuals with pathogenic variants in COL4A1/2, TREX1, HTRA1, ADA2 and CTSA genes (PROSPERO 74804). We included any publication reporting on ≥1 individual with a pathogenic variant and their clinically-relevant phenotype. We extracted individuals’ characteristics, and information about associated extracerebral phenotypes and stroke/TIA. We noted any novel extra-cerebral phenotypes and looked for shared phenotypes between monogenic cSVDs.
Results: After screening 6048 publications, we included 96 COL4A1 (350 individuals), 32 TREX1 (115 individuals), 43 HTRA1 (38 homozygous/61 heterozygous individuals), 16 OL4A2 (37 individuals), 119 ADA2 (209 individuals) and 3 CTSA (14 individuals) publications. The majority of individuals originated from Europe/North America, except for HTRA1, where most were from Asia. Age varied widely, ADA2 individuals being youngest and heterozygous HTRA1/CTSA individuals oldest. Sex distribution appeared equal. Extracerebral phenotypes were common: 14% to 100% of individuals with a pathogenic variant manifested at least one extra-cerebral phenotype (14% COL4A2, 43% HTRA1 heterozygotes, 47% COL4A1, 57% TREX1, 91% ADA2, 94% HTRA1 homozygotes and 100% CTSA individuals). Indeed, for 4 of 7 genes an extra-cerebral phenotype was observed more frequently than stroke/TIA. Ocular, renal, hepatic, muscle and hematological systems were each involved in more than one monogenic cSVD.
Conclusions: Extra-cerebral phenotypes are common in monogenic cSVD with extracerebral system involvement shared between genes. However, inherent biases in the existing literature mean that further data from large-scale population-based longitudinal studies collecting health outcomes in a systematic unbiased way is warranted. The emerging knowledge will help to select patients for testing, inform clinical management, and provide further insights into the underlying mechanisms of cSVD.
Original languageEnglish
Early online date26 Aug 2020
Publication statusE-pub ahead of print - 26 Aug 2020


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