TY - JOUR
T1 - A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds
AU - Cohn-Hokke, Petra E.
AU - Holstege, Henne
AU - Weiss, Marjan M.
AU - van der Flier, Wiesje M.
AU - Barkhof, Frederik
AU - Sistermans, Erik A.
AU - Pijnenburg, Yolande A.L.
AU - van Swieten, John C.
AU - Meijers-Heijboer, Hanne
AU - Scheltens, Philip
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - cavernoma
KW - cerebral cavernous malformations
KW - cognitive impairment
KW - familial clustering
KW - genetics
UR - http://www.scopus.com/inward/record.url?scp=84973904805&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ajmg.b.32468
DO - https://doi.org/10.1002/ajmg.b.32468
M3 - Article
C2 - 27277535
SN - 1552-4841
VL - 174
SP - 220
EP - 226
JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
IS - 3
ER -