Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants

Abstract

Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are familial with germline variants in one of three CCM genes—KRIT1/CCM1, CCM2 and PDCD10/CCM3. We performed comprehensive phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM. In the familial cases, initial standard analyses had a low yield, we therefore searched for small copy number changes and deep intronic variants. Subsequently, pathogenic germline variants in KRIT1/CCM1 or CCM2 were identified in all 9 multiplex..