High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one‐third of probands are minors

• Published in: Molecular genetics & genomic medicine 2014-03, Vol.2 (2), p.176-185
• Main Authors: Spiegler, Stefanie, Najm, Juliane, Liu, Jian, Gkalympoudis, Stephanie, Schröder, Winnie, Borck, Guntram, Brockmann, Knut, Elbracht, Miriam, Fauth, Christine, Ferbert, Andreas, Freudenberg, Leonie, Grasshoff, Ute, Hellenbroich, Yorck, Henn, Wolfram, Hoffjan, Sabine, Hüning, Irina, Korenke, G. Christoph, Kroisel, Peter M., Kunstmann, Erdmute, Mair, Martina, Munk‐Schulenburg, Susanne, Nikoubashman, Omid, Pauli, Silke, Rudnik‐Schöneborn, Sabine, Sudholt, Irene, Sure, Ulrich, Tinschert, Sigrid, Wiednig, Michaela, Zoll, Barbara, Ginsberg, Mark H., Felbor, Ute
• Format: Article
• Language: English
• Subjects: Age; Age at disease onset; Cases (containers); CCM1; CCM2; CCM2 protein; CCM3; cerebral cavernous malformation; Epilepsy; Families & family life; Genes; Genetic counseling; Genetic screening; Genetics; Genomes; Headache; HEG1; Hemorrhage; Lesions; Magnetic resonance imaging; Medical research; Mutation; mutation detection rate; Neurological diseases; Original; Pathogenicity; Pathogens; predictive testing; Protein expression; Proteins; Signs and symptoms; Software; Stroke
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.60

Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty‐one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In‐frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in‐frame deletion within the C‐terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue. Stringent inclusion criteria, comprehensive molecular genetic testing of CCM1, CCM2, and CCM3 and subsequent functional analysis yield very high mutation detection rates for familial and isolated cerebral cavernous malformations (CCM). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. In particular, parents of children with severe disease courses request predictive genetic testing of siblings.