Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity

Abstract

The molecular basis of familial retinal arteriolar tortuosity was identified for the first time, thus expanding the human phenotypes linked to COL4A1 mutations. Interestingly, the COL4A1 p.Gly510Arg mutation has been previously identified in a family with HANAC (Hereditary Angiopathy with Nephropathy, Aneurysm and Cramps), a multisystemic disease featuring retinal arteriolar tortuosity. No cerebral, neurologic, renal, cardiac or vascular anomalies were recognized in the pedigree described here. These data indicate that identical mutations in COL4A1 can originate both eye-restricted and systemic phenotypes.

Familial retinal arteriolar tortuosity and quantification of vascular tortuosity using swept-source optical coherence tomography angiography

“…While an exact etiology is not yet known, recent evidence suggests that a heterozygous mutation in COL4A1 may be causative in some cases of FRAT. COL4A1 has been thought to contribute to the production of collagen-based basement membrane proteins 1 . Interestingly, there are other systemic conditions due to COL4A1 mutations with retinal arteriolar tortuosity as a feature, including hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome 3 …”

“…The long-term visual prognosis is usually excellent. The condition has been associated with a missense mutation in the COL4A1 gene, which encodes a component of type IV collagen 1 . COL4A1 mutations have been found to cause COL4A1-related brain small-vessel disease, familial porencephaly, and hereditary angiopathy with nephropathy, aneurysms and muscle cramp (HANAC) syndrome.…”

Familial Retinal Arteriolar Tortuosity with Acute Hippocampal Infarction

“…Furthermore, an association with a heterozygous missense mutation in the COL4A1 gene, which encodes type IV collagen in the basal lamina of various ocular structures and vascular basement membranes, was reported in a family with HANAC (hereditary angiopathy with nephropathy, aneurysm, and muscle cramps). This gene mutation impairs collagen secretion and accumulates misfolded proteins within cells [7]. Such evidence suggests that the vascular malformation may not be limited to the retina.…”

A novel Cx50 (GJA8) p.H277Y mutation associated with autosomal dominant congenital cataract identified with targeted next-generation sequencing

“…1a). As described previously, the exon regions of these 60 genes, including the Cx50 gene (gap junction protein alpha 8, GJA8), were specifically enriched using biotinylated capture probe (MyGenostics, Baltimore, MD, USA) [17,18].…”