Objective: To detect the founder effect between familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) patients with (TTTTA)exp(TTTCA)exp (exp, expansion) in SAMD12 and healthy controls with pure (TTTTA)exp in SAMD12.

Background: Founder effect has been reported among FCMTE1 patients with (TTTTA)exp(TTTCA)exp in SAMD12 from different countries including China, Japan, India, Sri Lanka and Thailand. In SCA37-DAB1 locus, it was reported that similar repeat expansion – (TTTTA)exp(TTTCA)exp(TTTTA)exp shares a founder with pure (TTTTA)exp. The relationship between (TTTTA)exp(TTTCA)exp and pure (TTTTA)exp in FCMTE1-SAMD12 locus remains uncertain.

Method: Haplotype analysis at the core haplotype surrounding the FCMTE1-SAMD12 locus was extended among 11 reported families with FCMTE1 from five different countries and 29 unreported haplotypes including 16 with (TTTTA)exp(TTTCA)exp, 12 with pure (TTTTA)exp, and one with (TTTTA)13(TTTCA)exp(TTTTA)exp. The ages of the most recent common ancestor (MRCA) of different haplotype clusters were estimated based on the lengths of shared regions using an algorithm (Genetic Mutation Age Estimator: https://shiny.wehi.edu.au/rafehi.h/mutation-dating/) that makes use of recombination rates. Phylogenetic tree was built based on haplotype clusters and the estimated ages of MRCAs for different haplotype clusters.

Results: The core haplotype was shared in all 40 haplotypes, supporting the notion of a common founder of (TTTTA)exp(TTTCA)exp and pure (TTTTA)exp [Figure 1]. The pure (TTTTA)exp haplotypes were scattered among the different (TTTTA)exp(TTTCA)exp clusters. The estimated age of the MRCA for the 27 (TTTTA)exp(TTTCA)exp haplotypes was about 550.8 generations (95% confidence interval (CI): 421.6–720.5), whereas the estimated age of the MRCA for the 12 solo (TTTTA)exp haplotypes was about 636.6 generations (95% CI: 425.6–955.3 generations) [Table 1].

Conclusion: Our study contain the largest cohort of FCMTE1 patients and healthy controls with pure (TTTTA)exp in FCMTE1-SAMD12 locus. Here, we proposed that founder effects existed in all FCMTE1 patients with (TTTTA)exp(TTTCA)exp and healthy controls with pure (TTTTA)exp in FCMTE1-SAMD12 locus. However the evolutionary history between (TTTCA)exp and (TTTTA)exp requires further study.

References: 1. Cen Z, Jiang Z, Chen Y, et al. Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1. Brain. 2018;141(8):2280-2288.  2. Loureiro JR, Oliveira CL, Mota C, et al. Mutational mechanism for DAB1 (ATTTC)ninsertion in SCA37: ATTTT repeat lengthening and nucleotide substitution. Hum Mutat. 2019;40(4):404-412.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/founder-effect-in-ttttaexptttcaexp-and-pure-ttttaexp-in-familial-cortical-myoclonic-tremor-with-epilepsy-type-1-samd12-locus/