Table 1.

Monogenic cSVDs

Disease	Gene	Gene function	Vascular pathology	Clinical symptoms	Refs.
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) (OMIM: 125310)	NOTCH3	Encodes NOTCH3 transmembrane receptor that is involved in arterial differentiation and vascular smooth muscle cell remodeling.	NOTCH3 ectodomain aggregation and accumulation in the extracellular space of small vessels, intimal thickening, degeneration of SMCs.	Subcortical lacunar infarcts, vascular dementia, migraine with aura, psychiatric disturbances.	48, 78–80
CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) (OMIM: 600142)	HTRA1	Encodes High temperature requirement protein A1, a serine protease. Loss of HTRA1 function is associated with dysregulation of the TGF-β pathway. Emerging evidence suggest that heterozygous mutations also can cause early onset cSVD.	TGF-β signaling has a key role in vessel development and maintenance, acting in both endothelial and SMCs. Pathological studies showed extensive loss of SMC and deposition of fibro-hyaline material in the media.	Subcortical lacunar infarcts, vascular dementia, alopecia, spondylosis.	81–83
COL4-related angiopathies (OMIM: 607595; 614519)	COL4A1, COL4A2	Encodes alpha1 and alpha2 collagen chains, which are important components of the extracellular matrix.	Basement membrane abnormalities.	ICH, infantile hemiparesis, Axenfeld-Rieger anomaly, nephropathy, porencephalopathy.	27, 84
RVCL-S (retinal vasculopathy with cerebral leukodystrophy and systemic manifestations) (OMIM: 192315)	TREX1	Encodes DNase III, which plays a role in DNA repair.	Basement membrane defects in capillaries.	Retinal vasculopathy, subcortical lacunar infarcts, white matter hyperintensities, pseudotumors, migraine, cognitive impairment, psychiatric disturbances.	85, 86
FOXC1/PITX2-related SVD	FOXC1, PITX2	FOXC1 encodes forkhead box transcription factor C1, which is involved in blood vessel development. PITX2 encodes paired-like homeodomain transcription factor 2, which is involved in left-right asymmetry of internal organs. FOXC1 interacts with PITX2.	Changed endothelial and pericyte proliferation and impaired blood-brain barrier integrity in animal models.	Stroke, WMH, Axenfield-Rieger anomaly.	87–89
Deficiency of ADA2 (DADA2)	CECR1	Encodes adenosine deaminase 2 (ADA2). ADA2 plays a role in downregulation of extracellular adenosine, and cellular proliferation and differentiation.	Neutrophils and macrophages in interstitium with perivascular T-lymphocytes.	Small subcortical ischemic and hemorrhagic strokes, intermittent fevers, raised acute phase proteins, livedoid rash, hepatosplenomegaly	90, 91
CARASAL (cathepsin A related arteriopathy with strokes and leukoencephalopathy)	CTSA	Encodes cathepsin A, which is involved in the lysosomal transport, activation, and stabilization of β-galactosidase and neuraminidase-1. Cathepsin A inactivates selected neuropeptides and regulates a lysosomal pathway of protein degradation.	Fibrous thickening of the small vessels.	Subcortical ischemic and hemorrhagic strokes, cognitive impairment, swallowing difficulties, dry eyes and mouth, muscle cramps, treatment-resistant hypertension	92, 93