Autosomal dominant cerebral cavernous malformations (ccM) are leaky vascular lesions that can cause epileptic seizures and stroke-like symptoms. Germline mutations in either CCM1, CCM2 or CCM3 are found in the majority of patients with multiple CCMs or a positive family history. Recently, the first copy number neutral inversion in CCM2 has been identified by whole genome sequencing in an apparently mutation-negative CCM family. We here asked the question whether further structural genomic rearrangements can be detected within nGS gene panel data of unsolved ccM cases. Hybrid capture nGS data of eight index patients without a pathogenic single nucleotide, indel or copy number variant were analyzed using two bioinformatics pipelines. In a 58-year-old male with multiple CCMs in his brain and spinal cord, we identified a 294 kb insertion within the coding sequence of CCM2. fine mapping of the breakpoints, molecular cytogenetic studies, and multiplex ligation-dependent probe amplification verified that the structural variation was an inverted unbalanced insertion that originated from 1p12-p11.2. As this rearrangement disrupts exon 6 of CCM2 on 7p13, it was classified as pathogenic. Our study demonstrates that efforts to detect structural variations in known disease genes increase the diagnostic sensitivity of genetic analyses for well-defined Mendelian disorders. Cerebral cavernous malformations (CCM; MIM: 116860, 603284, 603285) are irregular clusters of enlarged and thin-walled vessels that can present as sporadic or autosomal dominant cerebrovascular disease. Aside from epileptic seizures and headaches, CCM patients may present with stroke-like symptoms due to chronic or acute bleeding events 1. Pathogenic germline variants have been identified in CCM1 (also known as KRIT1) 2,3 , CCM2 4,5 , and CCM3 (PDCD10) 6. The mutational spectrum primarily includes nonsense, frameshift, splice, and copy number variants (CNVs). 282 unique CCM1, 84 CCM2 and 75 CCM3 variants are classified as disease-causing in the Human Gene Mutation Database (HGMD Professional 2019.3) 7. Depending on the inclusion criteria for genetic analyses, mutation detection rates of 87 to 98% have been reported for familial CCM cases and up to 60% for sporadic ones 8-11. The mutation detection rate in the latter group could even be higher if patients with associated developmental venous anomalies or a history of radiotherapy to the brain were excluded 1,12. Although pathogenic variants in a yet unknown CCM4 candidate gene have been discussed for unresolved cases 13 , we recently were able to identify the first copy number neutral inversion in CCM2 in an apparently mutation-negative CCM family by whole genome sequencing (WGS) 14. Disease-causing structural variants (SVs) may explain a part of the "missing heritability" in rare diseases 15. SVs are defined as structural and quantitative chromosomal rearrangements that compromise cytogenetically visible and submicroscopic variants 16,17. They contribute to phenotypic variation but can also cause human diseas...