Whole Exome Sequencing in Patients with Phenotypically Associated Familial Intracranial Aneurysm.

OBJECTIVE

Familial intracranial aneurysms (FIAs) are found in approximately 6%-20% of patients with intracranial aneurysms (IAs), suggesting that genetic predisposition likely plays a role in its pathogenesis. The aim of this study was to identify possible IA-associated variants using whole exome sequencing (WES) in selected Korean families with FIA.

MATERIALS AND METHODS

Among the 26 families in our institutional database with two or more IA-affected first-degree relatives, three families that were genetically enriched (multiple, early onset, or common site involvement within the families) for IA were selected for WES. Filtering strategies, including a family-based approach and knowledge-based prioritization, were applied to derive possible IA-associated variants from the families. A chromosomal microarray was performed to detect relatively large chromosomal abnormalities.

RESULTS

Thirteen individuals from the three families were sequenced, of whom seven had IAs. We noted three rare, potentially deleterious variants ( c.1315G>A, c.968C>T, and c.58C>T), which are the most promising candidates among the 11 potential IA-associated variants considering gene-phenotype relationships, gene function, co-segregation, and variant pathogenicity. Microarray analysis did not reveal any significant copy number variants in the families.

CONCLUSION

Using WES, we found that rare, potentially deleterious variants in , , and genes are likely responsible for the subsets of FIAs in a cohort of Korean families.