The heritability and genetics of frontotemporal lobar degeneration

TLDR

Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. The study examined heritability in 225 FTLD patients by scoring family history and screening for mutations in MAPT, GRN, VCP, CHMP2B, TARDP, and FUS. Approximately 42 % of patients had a family history, with only 10 % showing a clear autosomal dominant pattern; heritability differed across FTLD subtypes, being highest in the behavioral variant, and MAPT and GRN mutations were found in 8.9 % and 8.4 % of the cohort, respectively, while other genes remain undiscovered.

Abstract

<b>Background:</b> Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. <b>Methods:</b> We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (<i>MAPT, GRN, VCP, CHMP2B</i>, and <i>TARDP</i>) and the <i>FUS</i> gene, known to cause motor neuron disease. <b>Results:</b> A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia–motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in <i>MAPT</i> (8.9% of the cohort) and <i>GRN</i> (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without <i>GRN</i> mutations (6) and FTLD-UPS (1). <b>Conclusion:</b> These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while <i>MAPT</i> and <i>GRN</i> mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a <i>GRN</i> mutation.