A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds.

Autor: Cohn-Hokke PE; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands., Holstege H; 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., Weiss MM; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands., van der Flier WM; 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., Barkhof F; Department of Radiology & Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands., Sistermans EA; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands., Pijnenburg YA; Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands., van Swieten JC; 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., Meijers-Heijboer H; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands., Scheltens P; Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics [Am J Med Genet B Neuropsychiatr Genet] 2017 Apr; Vol. 174 (3), pp. 220-226. Date of Electronic Publication: 2016 Jun 08.
DOI: 10.1002/ajmg.b.32468
Abstrakt: 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.
(© 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
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