Exome Sequencing Identifies LOXL2 Mutation as a Cause of Familial Intracranial Aneurysm

BACKGROUND: Genetic risk factors can contribute to the etiology of intracranial aneurysms (IAs), and the genetic predisposition of IAs is largely unknown. Our study aimed to explore the role of rare variations in IA susceptibility. METHODS: Whole-exome sequencing (WES) was performed in a representative family with a history of multiple cases of IAs. WES variants were prioritized by various filtering strategies, including frequency, predicted pathogenicity, and functional prediction. Sanger sequencing also was performed in an additional 2 families and sporadic IA cases. RESULTS: After WES and filtering, 15 single-nucleotide variants and 3 insertion/deletions (indels) were prioritized in the family. Among them, we selected 5 candidate variants (located in DHRS3, OR2G3, LOXL2, FGL1, and KLC3) by considering known disease genes or ontology association with cardiovascular morphogenesis or other known diseases. Genotyping results revealed that only c.C133T/p. H45Y in exon 2 of LOXL2 gene was segregated fully with definite IA phenotypes in the family. Moreover, LOXL2 has been reported as a susceptibility gene for IAs. CONCLUSIONS: LOXL2 c. C133T is a pathogenic mutation that is responsible for a fraction of familial IAs.