A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds.
Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid-beta-42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE-ϵ4; one heterozygous. The cognitive complaints, reduced amyloid-beta-42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Petra E
PE
Cohn-Hokke
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.|Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Henne
H
Holstege
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Marjan M
MM
Weiss
Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.|Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
Wiesje M
WM
van der Flier
Department of Radiology & Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Frederik
F
Barkhof
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Erik A
EA
Sistermans
Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Yolande A L
YA
Pijnenburg
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.|Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.|Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
John C
JC
van Swieten
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Hanne
H
Meijers-Heijboer
Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Philip
P
Scheltens
D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000235:genetics; D003071:Cognition; D003072:Cognition Disorders / Q000235:genetics; D003704:Dementia / Q000209:etiology / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017422:Sequence Analysis, DNA
D016229:Amyloid beta-Peptides; C502544:CCM2 protein, human; D002352:Carrier Proteins
cavernoma; cerebral cavernous malformations; cognitive impairment; familial clustering; genetics