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

• Published in: Neurobiology of aging Vol. 97; pp. 148.e9 - 148.e16
• Main Authors: Mol, Merel O., van Rooij, Jeroen G.J., Wong, Tsz H., Melhem, Shamiram, Verkerk, Annemieke J.M.H., Kievit, Anneke J.A., van Minkelen, Rick, Rademakers, Rosa, Pottier, Cyril, Kaat, Laura Donker, Seelaar, Harro, van Swieten, John C., Dopper, Elise G.P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021
• Subjects: Familial; Frontotemporal dementia; Genetic screen; Whole-exome sequencing; Frontotemporal dementia; Genetic screen; Familial; Whole-exome sequencing
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2020.07.014

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. •One of the largest genetic screens of familial frontotemporal dementia.•Three novel variants in GRN and a novel homozygous variant in OPTN.•Remarkably large proportion of patients with a TARDBP variant.•Fifteen variants of uncertain significance in less common frontotemporal dementia–related genes.•Large clinical and pathological heterogeneity of patients without genetic cause.