Abstract
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.
Highlights
Frontotemporal dementia (FTD) is one of the main causes of presenile dementia (Coyle-Gilchrist et al, 2016)
The most common cause was the C9orf72 repeat expansion identified in 21% (42/198), followed by pathogenic variants in MAPT in 6% (11/198; 6 unique variants), GRN in 4.5% (9/198; 8 unique variants, 3 of which were not reported previously), and TARDBP in 3.5% (7/198, 2 unique variants)
No cases were identified with a double pathogenic variant, this could not be excluded in 38 cases tested for single genes
Summary
Frontotemporal dementia (FTD) is one of the main causes of presenile dementia (Coyle-Gilchrist et al, 2016). FTD constitutes a heterogeneous spectrum with large variability in clinical and pathological features (Mackenzie and Rademakers, 2007; Mann and Snowden, 2017). It has a strong genetic component, and autosomal dominant inheritance is observed in 10%e25% of patients (Convery et al, 2019; Seelaar et al, 2008). Around two-thirds of familial cases remain without a known genetic cause, implying yet undiscovered variants (Pottier et al, 2019)
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