TY - JOUR
T1 - High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors
AU - Spiegler, Stefanie
AU - Najm, Juliane
AU - Liu, Jian
AU - Gkalympoudis, Stephanie
AU - Schröder, Winnie
AU - Borck, Guntram
AU - Brockmann, Knut
AU - Elbracht, Miriam
AU - Fauth, Christine
AU - Ferbert, Andreas
AU - Freudenberg, Leonie
AU - Grasshoff, Ute
AU - Hellenbroich, Yorck
AU - Henn, Wolfram
AU - Hoffjan, Sabine
AU - Hüning, Irina
AU - Korenke, G. Christoph
AU - Kroisel, Peter M.
AU - Kunstmann, Erdmute
AU - Mair, Martina
AU - Munk-Schulenburg, Susanne
AU - Nikoubashman, Omid
AU - Pauli, Silke
AU - Rudnik-Schöneborn, Sabine
AU - Sudholt, Irene
AU - Sure, Ulrich
AU - Tinschert, Sigrid
AU - Wiednig, Michaela
AU - Zoll, Barbara
AU - Ginsberg, Mark H.
AU - Felbor, Ute
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
U2 - 10.1002/mgg3.60
DO - 10.1002/mgg3.60
M3 - Journal articles
C2 - 24689081
SN - 2324-9269
VL - 2
SP - 176
EP - 185
JO - Molecular Genetics & Genomic Medicine
JF - Molecular Genetics & Genomic Medicine
IS - 2
ER -