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© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.

The challenges inherent in diagnosing and treating patients with Alzheimer's disease are increasing. Early diagnosis and modification of risk factors have received growing attention from the media in recent years. As a result, the general public, and patients and family members, are increasingly better informed about the disease, its genetic background, and the possibilities for treatment. The physician is often faced with questions about hereditary patterns within the family and with requests to perform genetic testing. Children, with increasing frequency, ask for a separate appointment with the treating physician, during the patient's life or after the patient has died, to discuss whether they are likely to get the disease and whether genetic tests should be performed. In this paper, some of the clinical and ethical questions that physicians face are explored. Arguments as to why we think routine genetic assessment should not be part of the diagnostic examination of the patient suspected of Alzheimer's disease are given.

Familial forms of frontotemporal dementia (FTD) with tauopathy are mostly caused by mutations in the gene encoding the microtubule-associated protein tau (MAPT). However, rare forms of familial tauopathy without MAPT mutations have been reported, suggesting other tauopathy-related genetic defects. Interestingly, two presenilin I (PSI) mutations (Leu113Pro and insArg352) recently have been associated with familial FTD albeit without neuropathological confirmation. We report here a novel PSI mutation in a patient with Pick-type tauopathy in the absence of extracellular beta-amyloid deposits. The mutation is predicted to substitute Gly-->Val at codon position 183 (Gly183Val) and to affect the splice signal at the junction of the sixth exon and intron. Further clinical-genetic investigation showed a positive family history of FTD-like dementia and suggested that Gly183Val is associated with a phenotypically heterogeneous neurodegenerative disorder. Our results suggest PSI as a candidate gene for Pick-type tauopathy without MAPT mutations.

We analyzed the PRNP M129V polymorphism in a Dutch population-based early-onset Alzheimer's disease sample. We observed a significant association between early-onset Alzheimer's disease and homozygosity of M129V (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.3; P = 0.02) with the highest risk for V homozygotes (OR, 3.2; 95% CI, 1.4-7.1; p < 0.01). In patients with a positive family history, these risks increased to 2.6 (95% CI, 1.3-5.3; p < 0.01) and 3.5 (95% CI, 1.3-9.3; p = 0.01), respectively.

We report the cytogenetic findings in a case of mixed germ cell-sex cord-stromal tumor of the ovary in a 5-month-old girl. Monosomy 22 was observed as the sole karyotypic abnormality. This result was confirmed by comparative genomic hybridization, which revealed no additional chromosomal imbalances. This is the first observation of a chromosomal aberration in a mixed germ cell-sex cord-stromal tumor of the ovary. Monosomy 22 has been previously observed in granulosa cell tumors of the ovary. This could suggest a common pathogenetic pathway for both types of tumors.