(TTTCA)exp Drives the Genotype-Phenotype Correlation and Genetic Anticipation in FCMTE1.

Background: The pentanucleotide (TTTCA) repeat expansion (exp) insertion, along with the accompanying (TTTTA)exp, causes familial cortical myoclonic tremor with epilepsy (FCMTE). The genotype-phenotype correlations and intergenerational instabilities related to (TTTCA)exp and (TTTTA)exp are still unclear.

Objective: The aim was to investigate the genotype-phenotype correlations and intergenerational instabilities related to (TTTCA)exp and (TTTTA)exp in FCMTE1.

Methods: We performed targeted long-read sequencing on 77 FCMTE1 patients. After quality control, metrics such as total repeat count, respective (TTTTA)exp and (TTTCA)exp count, and interruptions were assessed in 73 patients. Correlations between metrics and the patients' clinical features, as well as repeat instability during parental transmission, were analyzed.

Results: Among 73 alleles, the average total repeat counts were 848 ± 152 units, with (TTTTA)exp and (TTTCA)exp averaging 498 ± 196 units and 356 ± 110 units, respectively. (TTTCA)exp counts were inversely correlated with the age at onset for cortical tremor (Spearman's rho = -0.348, P = 0.005) and epilepsy (Spearman's rho = -0.424, P = 0.003). A negative correlation was found between (TTTCA)exp counts and relatively moderate seizure pattern with prodrome (odds ratio = 0.988, 95% confidence interval: 0.980-0.995, P = 0.002). During parental transmission, (TTTCA)exp counts increased significantly (P = 0.007), with maternal transmission showing a significantly larger increase compared to paternal transmission (P = 0.013).

Conclusion: The (TTTCA)exp insertion serves as the length-dependent pathogenic component within the two-motif repeat expansion. Its differential expanding nature during parental transmissions is highly associated with the genetic anticipation in FCMTE1. © 2024 International Parkinson and Movement Disorder Society.