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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\u2010beta\u201042 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 <jats:italic>CCM2<\/jats:italic> 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 <jats:italic>APOE\u2010\u03f54<\/jats:italic>; one heterozygous. The cognitive complaints, reduced amyloid\u2010beta\u201042 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 <jats:italic>CCM2<\/jats:italic> variant and the <jats:italic>APOE<\/jats:italic> status. \u00a9 2016 The Authors. <jats:italic>American Journal of Medical Genetics Part B: Neuropsychiatric Genetics<\/jats:italic> Published by Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.b.32468","type":"journal-article","created":{"date-parts":[[2016,6,9]],"date-time":"2016-06-09T05:00:34Z","timestamp":1465448434000},"page":"220-226","source":"Crossref","is-referenced-by-count":4,"title":["A novel <i>CCM2<\/i> variant in a family with non\u2010progressive cognitive complaints and cerebral microbleeds"],"prefix":"10.1002","volume":"174","author":[{"given":"Petra E.","family":"Cohn\u2010Hokke","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics VU University Medical Center Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henne","family":"Holstege","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics VU University Medical Center Amsterdam The Netherlands"},{"name":"Alzheimer Center, Department of Neurology, VU University Medical Center Neuroscience Campus Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjan M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics VU University Medical Center Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wiesje M.","family":"van der Flier","sequence":"additional","affiliation":[{"name":"Alzheimer Center, Department of Neurology, VU University Medical Center Neuroscience Campus Amsterdam Amsterdam The Netherlands"},{"name":"Department of Epidemiology and Biostatistics VU University Medical Center Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"Department of Radiology &amp; Nuclear Medicine, VU University Medical Center Neuroscience Campus Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik A.","family":"Sistermans","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics VU University Medical Center Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yolande A. 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