A Complex FGF14 ( TTC )/( TGC ) Repeat Expansion in Parkinson's Disease

Background Repeat expansions have been reported as genetic causes/risk factors of Parkinson's disease (PD). As a novel repeat expansion locus, the FGF14‐SCA27B (GAA)•(TTC) repeat locus is unexplored in PD. Methods Utilizing genetic sequencing and various polymerase chain reaction (PCR) methodologies, pure and complex repeat expansions in FGF14 were detected in Asian PD patients. Targeted long—read sequencing was performed to investigate the detailed sequence composition of these repeat expansions. Case–control studies were further performed. Results Pure (TTC) ≥250 repeat expansion was detected in 2 of 1190 PD patients (0.17%). Additionally, a more common and complex (TTC)/(TGC) ≥300 repeat expansion was detected as the main expanded genotype in our discovery cluster. Using targeted long‐read sequencing, these complex (TTC)/(TGC) repeat expansions were characterized as (TTC)exp(TGCTTC)exp(TGCTTCTTCTTCTTC)n(TTC)n alleles with four segments (Seg 1–4), and further classified into four genotypic patterns. Pattern 1 was mainly characterized by a (CTC) interruption in the Seg 1‐(TTC)exp. Patterns 2–4 were characterized by different repeat length of Seg 1‐(TTC)exp and Seg 3‐(TGCTTCTTCTTCTTC)n. Case–control analysis revealed a significant enrichment of Pattern 4 (TTC)/(TGC) repeat expansion in PD compared with controls ( P = 0.024, OR: 2.60, 95% CI: 1.07–7.23) in the discovery cluster. This significant association between Pattern 4 (TTC)/(TGC) repeat expansion and PD was confirmed in one of two replication clusters ( P = 0.035, OR: 2.18, 95% CI: 0.95–4.53) and the meta‐analysis across all three clusters ( P = 0.015, OR: 1.75, 95% CI: 1.10–2.79). Interpretation We identified a unique complex (TTC)/(TGC) repeat expansion in FGF14 as a novel genetic risk factor of PD in the Asian population.