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 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), 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/transient ischemic attack. We noted any novel extracerebral 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
COL4A2
(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 extracerebral 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 extracerebral phenotype was observed more frequently than stroke/transient ischemic attack. Ocular, renal, hepatic, muscle, and hematologic systems were each involved in more than one monogenic cSVD.
Conclusions:Extracerebral 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.
