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.