Familial cerebral cavernous malformations caused by a novel germline structural variant in the KRIT1 gene

The detection of complex structural variants in patients with familial cerebral cavernous malformations (FCCM) remains challenging. Short-read whole genome sequencing was performed for a patient with strong clinical evidence of FCCM but negative results from previous genetic tests. The analysis revealed a large insertion of an intronic KRIT1 fragment into a coding exon of KRIT1. This novel structural variant results in a frameshift and was classified as pathogenic. Predictive testing can now be offered to asymptomatic family members. This case expands the known mutation spectrum in FCCM and suggests that, after negative whole exome or gene panel sequencing, whole genome sequencing should be offered as a second-line diagnostic test.