The genetic landscape of frontotemporal lobar degeneration: investigation of a diagnostic cohort of 2747 probands

Genetic factors play an important role in frontotemporal lobar degeneration (FTLD) with about 20 genes reported to be involved. Although it is known that genetic diagnostic yield depends on age at onset, clinical subtype and family history, there are no precise indication criteria for a cost-effective and efficient strategy in clinical setting. We report the molecular diagnostic experience in a French clinical laboratory in a large cohort of 2747 probands with sporadic or familial FTLD. We used a three-step genetic screening strategy. First, measurement of plasma progranulin assay was performed in all cases (n=2747), followed by screening of GRN when plasma progranulin was below the threshold. If GRN screening was negative, the second step consisted of the investigation of the G4C2 repeat expansion in C9orf72 (n= 2675). In a third step, targeted sequencing of 14 FTLD genes was performed in 1279 individuals depending on age at onset and family history. Diagnostic yield of this strategy was 12.2% (n=334). GRN (n=73) and C9orf72 (n=200) represent 81.7% of genetic diagnoses. Diagnostic yield of the panel sequencing was 4.8% (62/1279). Family history was the strongest factor related to genetic diagnosis, with four to five times more genetic diagnoses in cases with a family history of FTLD (32.1%) compared with sporadic cases (7.2%). Although the clinical presentation is not significantly associated with identifying a genetic mutation, behavioural variant of frontotemporal dementia (bvFTD) associated with amyotrophic lateral sclerosis (FTD/ALS) or not produced a higher diagnostic yield (15.5% and 13.3%, respectively) than the primary progressive aphasia subgroup (9.9% for semantic variant and 8.8% for non-fluent variant) and others (8.3% and 4.2% for progressive supranuclear palsy and corticobasal syndrome, respectively). Interestingly, the genetic distribution varies greatly between clinical subtypes. FTD/ALS and bvFTD were mostly driven by C9orf72 (82.1% and 63.5%, respectively). In contrast, GRN is the dominant gene in nfvPPA (41.2%). C9orf72, MAPT, GRN and TBK1 equally contributes to svPPA (around 20% each). These results allow us to show the phenotype-genotype architecture of FTLD and to provide data to establish a cost-effective genetic diagnostic strategy in clinical settings for FTLD.