title: Predictive genetic testing of at-risk relatives requires analysis of all CCM genes after identification of an unclassified CCM1 variant in an individual affected with cerebral cavernous malformations.
abstract: The mutation detection rate for familial cerebral cavernous malformations (CCM) is extremely high, being about 90 % if direct sequencing of the three genes, CCM1, CCM2, and CCM3, is used in conjunction with quantitative analyses to detect larger CCM1-3 deletions/duplications. We here report on an individual who had presented with more than 30 cerebral and spinal cavernous malformations, two intracranial meningiomas, and disease manifestation only in the mid-forties. A CCM1 missense variant of unclear relevance was found during the first sequencing step. Thereafter, direct sequencing of all three CCM genes revealed the typical pathogenic loss-of-function mutation c.598C > T/p.Q200* in the CCM3 gene. Our results demonstrate that mutation analyses of all three CCM genes in the index patient regardless of previous identification of an unclassified CCM1 variant is crucial for reliable predictive testing of at-risk relatives.
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, 17475, Greifswald, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Schröder
authors.forename: Juliane
authors.initials: J
authors.lastname: Najm
authors.forename: Stefanie
authors.initials: S
authors.lastname: Spiegler
authors.forename: Martina
authors.initials: M
authors.lastname: Mair
authors.forename: Julio
authors.initials: J
authors.lastname: Viera
authors.forename: Wolfram
authors.initials: W
authors.lastname: Henn
authors.forename: Ute
authors.initials: U
authors.lastname: Felbor
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D020786:Hemangioma, Cavernous, Central Nervous System / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D000075927:KRIT1 Protein; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D018570:Risk Assessment
chemical_list: D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins