Identity-by-Descent Analysis Uncovering a Founder Event in a Novel Hereditary Small Vessel Cerebral Disease

A novel genetic cerebral small vessel disease, linked to the insertion of a mobile genetic element in the COL4A1 gene has recently been identified. Notably, 8 out of the 10 families carrying this mutation were known to come from Brittany, a specific region in France, suggesting the possibility of a common ancestor and a founder effect.

Probands from each of the 10 families were analyzed with high-density single nucleotide polymorphism arrays. Bioinformatics tools were used to identify identical-by-descent chromosomal segments shared among probands.

Two of the 10 families were shown to be closely related. Furthermore, all probands shared a common identical-by-descent haplotype around the COL4A1 locus on 13q34, establishing the inheritance of the mutation from a single common ancestor. The most recent common ancestor of the 10 families is estimated to be born around 1735 (95% CI, 1600-1820) and is most probably of European descent.

This study demonstrates that this newly identified cerebral small vessel disease is the result of a founder effect, with strong clinical and epidemiological implications. This mutation is likely to be found mainly in regions with recent migratory ties to Brittany, such as the British Isles and North America, highlighting the need for further studies to assess the AluYa5 insertion in these areas. To our knowledge, this is the first reported instance of a founder effect contributing to a cerebral small vessel disease.