FCCM = familial cerebral cavernous malformations; NA = not applicable

Genes are listed in alphabetic order.

See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on variants detected in these genes.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

Riant et al [2013] and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

Variability in the detection rate of deletion/duplication testing results from the high prevalence of a founder CCM2 deletion (exons 2-10) in the United States. This deletion was rare in an Italian population [Liquori et al 2007, Liquori et al 2008]. To date, very few large intragenic deletions/duplications have been reported in individuals with FCCM. Cohorts who had no detectable KRIT1, CCM2, or PDCD10 pathogenic variant by sequence analysis had (multi)exon deletions of KRIT1 at a frequency of 5% in the US, 4% in France, and 50% in Italy [Liquori et al 2008, Riant et al 2013].

Following stringent inclusion criteria for FCCM (multiple lesions and/or family history consistent with FCCM), a heterozygous pathogenic variant in either KRIT1, CCM2, or PDCD10 is detected in at least 75% of affected families [Denier et al 2006, Liquori et al 2007, D'Angelo et al 2011, Riant et al 2013, Spiegler et al 2014], with some studies reporting ~97% detection rates [Cigoli et al 2014].