Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary stroke disorder. Mutations in NOTCH3 have been shown to cause this disease. We used exome sequencing to study a Swedish family (Figure) with a clinical picture similar to CADASIL, presenting with autosomal dominant cerebrovascular disease manifesting with transient ischaemic attacks/strokes, neuropsychiatric symptoms and progressive cognitive decline, but without mutations in NOTCH3.
By integrating results from genetic linkage analysis and exome sequencing we identified one non-coding variant (COL4A1:c.*32G>A) that was present in the patients and was absent in the healthy family members.
Even though these results were very compelling, it is not common to have 3’UTR variants located on miRNA binding sites as the cause of Mendelian diseases. In fact, we could only identify 6 other cases where variants in miRNA sequences, or in 3’UTR miRNA binding regions of target genes were shown to be the cause of Mendelian diseases (Table).
Supporting this finding, we demonstrated that the COL4A1:c.*32G>A mutation affects miR-29 binding, leading to upregulation of COL4A1. Additionally, Verdura et al. recently identified mutations in COL4A1 3’UTR as the cause of cerebral small vessel diseases (cSVD) in six families, including pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) cases that have very similar clinical characteristics to the Swedish family we studied. The mutations identified by Verdura et al. also affected the binding site for miR-29 within the 3’UTR of COL4A1.
These results widen the already large spectrum of phenotypes associated with COL4A1 mutations and potentially indicate a convergent pathologic pathway in monogenic small vessel diseases.