Familial cerebral small vessel disease

Gene: FOXC1

PMID: 32720677 - Ferre-Fernández et al 2020 - zebrafish knockout lines with combinations of the two orthologs of FOXC1 in zebrafish, foxc1a and foxc1b. 3 phenotypes:
1. foxc1a−/− single knockout homozygous embryos and foxc1−/− double knockout homozygous embryos - severe global vascular defects and early lethality, as well as microphthalmia, periocular edema and absence of the anterior chamber of the eye
2. fish with heterozygous loss of foxc1a combined with homozygosity for foxc1b (foxc1a+/−;foxc1b−/−) demonstrated craniofacial defects, heart anomalies and scoliosis
3. All other single and combined genotypes appeared normal.

Created: 6 Oct 2020, 3:56 p.m. | Last Modified: 6 Oct 2020, 3:56 p.m.

Panel Version: 1.9

Publications

• 32720677

Comment when marking as ready: Associated with phenotype in G2P. Numerous variants reported in this phenotype.

Created: 4 Jul 2016, 9:28 a.m.

Comment on list classification: Tier 1 gene for Cerebral Small Vessel Disorders in BRIDGE Study

Created: 4 Jul 2016, 9:19 a.m.

Green List (high evidence)

FOXC1-deletion related cerebral small vessel disease is caused by mutations or deletions in the FOXC1 gene (chromosome 6p25). FOXC1 deletions cause Axenfeld-Rieger Syndrome, cerebellar malformations and developmental abnormalities. These patients have also been shown to have white matter hyperintensities on MRI.

In multiple cases of Axenfeld-Rieger Syndrome and other FOXC1-deletion related syndromes, white matter hyperintensities on brain imaging have been reported.

In a genome-wide association analysis, linked SNPs which influence FOXC1 transcript levels and FOXC1 function were also demonstrated to associate with cerebral small vessel disease. Patients with missense and nonsense mutations, as well as duplications and deletions involving the FOXC1 region were also shown to have imaging features of cerebral small vessel disease.

Created: 22 Jun 2016, 3:07 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
stroke; Axenfled Rieger Syndrome, Cerebellar malformations; Dandy Walker Syndrome; Hearing Impairment

Publications

• PMID: 22678982
• 22903608
• 25250569
• 16551997
• 23686687