Underlying genetic variation in familial frontotemporal dementia: sequencing of 198 patients

Neurobiol Aging. 2021 Jan;97:148.e9-148.e16. doi: 10.1016/j.neurobiolaging.2020.07.014. Epub 2020 Jul 30.


Frontotemporal dementia (FTD) presents with a wide variability in clinical syndromes, genetic etiologies, and underlying pathologies. Despite the discovery of pathogenic variants in several genes, many familial cases remain unsolved. In a large FTD cohort of 198 familial patients, we aimed to determine the types and frequencies of variants in genes related to FTD. Pathogenic or likely pathogenic variants were revealed in 74 (37%) patients, including 4 novel variants. The repeat expansion in C9orf72 was most common (21%), followed by variants in MAPT (6%), GRN (4.5%), and TARDBP (3.5%). Other pathogenic variants were found in VCP, TBK1, PSEN1, and a novel homozygous variant in OPTN. Furthermore, we identified 15 variants of uncertain significance, including a promising variant in TUBA4A and a frameshift in VCP, for which additional research is needed to confirm pathogenicity. The patients without identified genetic cause demonstrated a wide clinical and pathological variety. Our study contributes to the clinical characterization of the genetic subtypes and confirms the value of whole-exome sequencing in identifying novel genetic variants.

Keywords: Familial; Frontotemporal dementia; Genetic screen; Whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cytoskeletal Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Exome Sequencing
  • Female
  • Frontotemporal Dementia / genetics*
  • Genetic Association Studies*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • Humans
  • Male
  • Membrane Transport Proteins / genetics
  • Presenilin-1 / genetics
  • Protein Serine-Threonine Kinases / genetics
  • Valosin Containing Protein / genetics
  • tau Proteins / genetics


  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • DNMBP protein, human
  • MAPT protein, human
  • Membrane Transport Proteins
  • OPTN protein, human
  • PSEN1 protein, human
  • Presenilin-1
  • TARDBP protein, human
  • tau Proteins
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • VCP protein, human
  • Valosin Containing Protein