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Page 6 of 30 Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16

Table 1. Representative genetic factors in VVs and venous leg ulcer
Gene chromosome Disease Manifestations Ref.
locus, variants
COL3A1, COL5A1, Ehlers-Danlos syndrome Connective tissue disorders, abnormal collagen synthesis, joint [39,224]
ADAMTS2 hypermobility, distensible skin, ocular disease, bone
deformities and fragility, vascular and visceral tissue wall
fragility and susceptibility to rupture, VVs
von-Hippel Lindau Chuvash polycythemia Defective oxygen sensing, increased HIF-1α, increased serum [225-227]
gene mutation erythropoietin and hemoglobin, VVs, tendency for vertebral
3p25 hemangiomas, thrombosis, bleeding, and stroke
598>T
G6PC3 gene mutation Severe congenital neutropenia VVs, venous leg ulcer [228]
type 4
Desmuslin gene VVs Decreased intermediate filament protein desmuslin in VSM, [48,117,120,229,230]
deficiency smooth muscle switch from contractile to synthetic phenotype,
15q26.3 weakening of vein wall, venous dilation. Increased MMP-2 and
collagen
Thrombomodulin (- Deep venous thrombosis, VVs Dysregulation of thrombin, thrombus formation [231]
1208/-1209 TT
deletion)
Translocation of Klippel-Trenaunay syndrome Cutaneous capillary [232,233]
chromosome 8q22.3 malformations (port wine stain), VVs, bone and soft tissues
& 14q13 hypertrophy
EII3K or VG5Q gene
mutation on
chromosome 5
FOXC2 gene mutation Lymphoedema distichiasis Lymphedema, distichiasis (extra eyelashes from meibomian [234-236]
16q24.3 glands), VVs, congenital heart defects, vertebral anomalies,
extradural cysts, ptosis, cleft palate
Notch3 gene mutation CADASIL Cerebral autosomal-dominant arteriopathy with subcortical [46]
1279G>T infarcts and leukoencephalopathy, VVs
Trisomies VVs Abnormalities in cell lines from patients with VVs [237]
chromosomes 7, 12, 18
Monosomy
chromosome 14
F13A1 gene Factor XIII deficiency Delayed venous ulcer healing [54]
HFE gene mutation Increased iron deposition Venous ulcer exacerbation [51]
C282Y and H63D
MTFR gene Decreased Hyperhomocystinemia, VVs, CVI [238,239]
SNP C677T methylenetetrahydrofolate
reductase activity
SLC40A1 Impaired iron metabolism, CVD, venous ulcer [240]
SNP 8CG increased iron deposition
MMP-12 Altered MMP activity Venous ulcer [240]
SNP 82AA
FGFR-2 mRNA instability, reduced CVI, non-healing venous ulcer [241]
SNP 2451AG wound healing

VVs: Varicose veins; VSM: vascular smooth muscle; MMP: matrix metalloproteinases; CADASIL: cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy; CVI: chronic venous insufficiency; CVD: chronic venous disease.

were robustly associated with VVs, including genes encoding for blood pressure, vascular mechanosensing
channels, vascular maturation, development and integrity, and genes near the hemochromatosis gene that is
strongly associated with VLU and DVT . Patients with Ehlers-Danlos syndrome show increased
[38]
propensity to developing vascular pathologies and VVs . Ehlers-Danlos syndrome includes several
[39]
connective tissue disorders that involve abnormal collagen synthesis and could be manifested in the form of
distensible skin, joint hypermobility, bone fragility and deformity, ocular disease, and cardiovascular and
visceral disorders in which the blood vessels and visceral tissue walls become more fragile and prone to
rupture. Patients with vascular Ehlers-Danlos syndrome have defective COL3A1 gene and are more
susceptible to vascular disease and VVs [39,40] . Of note, patients with hereditary connective tissue syndromes