Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling

Abstract

Based on the latest gnomAD dataset, the prevalence of symptomatic hereditary cerebral cavernous malformations (CCMs) prone to cause epileptic seizures and stroke-like symptoms was re-evaluated in this review and calculated to be 1:5,400-1:6,200. Furthermore, state-of-the-art molecular genetic analyses of the known CCM loci are described which reach an almost 100% mutation detection rate for familial CCMs if whole genome sequencing is performed for seemingly mutation-negative families. An update on the spectrum of CCM1, CCM2, and CCM3 mutations demonstrates that deep-intronic mutations and submicroscopic copy-number neutral genomic rearrangements are rare. Finally, this review points to current guidelines on genetic counselling, neuroimaging, medical as well as neurosurgical treatment and highlights the formation of active patient organizations in various countries.

Keywords: Cerebral cavernous malformations; Genetic counselling; Molecular genetics; Prevalence; Vascular malformation.

Fig. 1

T1-weighted (A) and T2-weighted (B) MRI of a 25-year-old proband with a cavernous malformation in his left posterior parietal lobe (red arrows). The Zabramski type II CCM with a maximum diameter of 23 mm shows the typical popcorn-like appearance and mixed signal intensities. The surrounding dark rim in T1 and T2 imaging is due to hemosiderin deposits.

Fig. 2

Spectrum and distribution of known mutations in CCM1, CCM2, and CCM3. The organization of the main transcripts is schematically depicted with blue boxes indicating protein coding exons, clear boxes representing non-coding exons, and blue lines indicating intronic sequences [exon numbering according to the locus reference genomic (LRG) database]. The last coding nucleotide of each exon is given below each box. Nonsense, frameshift, missense, and splice site mutations listed in HGMD 2017.2 are depicted in the upper part of each subpanel. Small deletions, insertions and indel variants that affect splicing have been classified as splice mutations. ATG, start codon; TGA, stop codon. Large deletions and insertions are not included.

Fig. 3

Comprehensive genetic screening of CCM1–3 by targeted capture enrichment and NGS. A Representative diagnostic NGS data from our own cohort (unpublished data). The read depth across the coding regions of CCM2 is shown as coverage plot (dark blue); exon-intron structures of the ENSEMBL-listed CCM2 transcripts are shown below. A chromosome ideogram with the cytogenetic location of CCM2 (red line) is depicted in the upper part and the GC content is illustrated with CpG islands in the lower part. B Representative NGS-based CNV analysis demonstrating a heterozygous deletion of exon 8 and 9 of CCM3.