[Gene mutations in patients with hereditary cavernous malformations]

To identify mutations in cerebral cavernous malformation (CCM) genes in patients with hereditary and sporadic CCMs in the Russian population.

Blood samples from 73 randomly selected patients, including 29 MRI-confirmed familial cases, 8 clinically confirmed familial cases and 38 so-called sporadic cases, were examined. A search for large deletions/duplications was performed using multiplex ligation-dependent probe amplification (MPLA). For MLPA-negative samples, the whole genome sequencing was performed to search for single nucleotide polymorphisms (SNP).

Deletions in three genes (ССМ1, ССМ2, ССМ3) were identified in 14 patients, including 5 without definitely established familial type, in whom the familial character of disease was not confirmed by clinical and neuroimaging results. SNP mutations were found in 13 patients, CCM gene mutations in 27. Mutations were detected in 91.7% of familial cases. In two patients, new CCM3 deletions were identified. Gene distribution was as follows: 60.7 for CCM1, 32.2 for CCM2 and 7.1% for CCM3. In two members of a family with hereditary CCMs, no high effect mutations in the known CCM genes were found. Patients with mutations had greater severity of disease. Two patients with CCM3 mutations demonstrated the most aggressive clinical course. De novo formation and growth of CCM were observed only in patients with mutations.

The distribution of pathogenic mutations in known CCM genes is consistent with other large-scale studies. Familial CCMs are associated with more severe disease course and may be caused by mutations beyond the known CCM genes.