Genetics of <scp>FTLD</scp>: overview and what else we can expect from genetic studies

<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>Frontotemporal lobar degeneration (<jats:styled-content style="fixed-case">FTLD</jats:styled-content>) comprises a highly heterogeneous group of disorders clinically associated with behavioral and personality changes, language impairment, and deficits in executive functioning, and pathologically associated with degeneration of frontal and temporal lobes. Some patients present with motor symptoms including amyotrophic lateral sclerosis. Genetic research over the past two decades in <jats:styled-content style="fixed-case">FTLD</jats:styled-content> families led to the identification of three common <jats:styled-content style="fixed-case">FTLD</jats:styled-content> genes (microtubule‐associated protein tau, progranulin, and chromosome 9 open reading frame 72) and a small number of rare <jats:styled-content style="fixed-case">FTLD</jats:styled-content> genes, explaining the disease in almost all autosomal dominant <jats:styled-content style="fixed-case">FTLD</jats:styled-content> families but only a minority of apparently sporadic patients or patients in whom the family history is less clear. Identification of additional <jats:styled-content style="fixed-case">FTLD</jats:styled-content> (risk) genes is therefore highly anticipated, especially with the emerging use of next‐generation sequencing. Common variants in the transmembrane protein 106 B were identified as a genetic risk factor of <jats:styled-content style="fixed-case">FTLD</jats:styled-content> and disease modifier in patients with known mutations. This review summarizes for each <jats:styled-content style="fixed-case">FTLD</jats:styled-content> gene what we know about the type and frequency of mutations, their associated clinical and pathological features, and potential disease mechanisms. We also provide an overview of emerging disease pathways encompassing multiple <jats:styled-content style="fixed-case">FTLD</jats:styled-content> genes. We further discuss how <jats:styled-content style="fixed-case">FTLD</jats:styled-content> specific issues, such as disease heterogeneity, the presence of an unclear family history and the possible role of an oligogenic basis of <jats:styled-content style="fixed-case">FTLD</jats:styled-content>, can pose challenges for future <jats:styled-content style="fixed-case">FTLD</jats:styled-content> gene identification and risk assessment of specific variants. Finally, we highlight emerging clinical, genetic, and translational research opportunities that lie ahead.</jats:p></jats:sec><jats:sec><jats:label /><jats:p> <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc13622-fig-0003-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> Genetic research led to the identification of three common FTLD genes with rare variants (<jats:italic>MAPT</jats:italic>,<jats:italic> GRN</jats:italic>, and <jats:italic>C9orf72</jats:italic>) and a small number of rare genes. Efforts are now ongoing, which aimed at the identification of rare variants with high risk and/or low frequency variants with intermediate effect. Common risk variants have also been identified, such as <jats:italic>TMEM106B</jats:italic>. This review discusses the current knowledge on FTLD genes and the emerging disease pathways encompassing multiple FTLD genes.</jats:p><jats:p><jats:bold>This article is part of the</jats:bold> <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1471-4159/homepage/special_issues.htm">Frontotemporal Dementia special issue</jats:ext-link>.</jats:p></jats:sec>