Objective: To investigate whether the hexamer repeat in the TCERG1 gene plays a role in modifying disease onset in X-linked dystonia-parkinsonism (XDP).

Background: Recently, it has been reported that the tandem hexamer repeat in exon 4 of TCERG1 (Transcription elongation regulator 1) modifies age at onset (AAO) of Huntington’s disease (HD) [1]. This hexameric coding repeat, referred to as a quasi-tandem repeat (QTR) hexamer, consists of a pure (CAGGCC) central repeat (short tandem repeat; STR) and two stretches of imperfect hexameric repeats on both sides of the STR. In HD patients, each added hexameric repeat reduces AAO by one year. XDP is an adult-onset neurodegenerative movement disorder endemic to the Philippines. HD and XDP are both repeat expansion diseases with clinical and neuropathological similarities. In addition, the AAO in HD and XDP are genetically modified by the same DNA mismatch-repair mechanism. Thus, we hypothesized that the QTR in TCERG1 also plays a role in modifying AAO in XDP.

Method: We performed Sanger sequencing of exon 4 of TCERG1 in 255 XDP patients. The alleles were classified based on the lengths of the QTR and STR. The AAO of XDP was then correlated with the length of the STR or the entire QTR, the sum of QTR lengths, or the difference in QTR lengths.

Results: In addition to the reference allele A1 (STRn=6, QTRn=38), we detected 5 alternative alleles (A2: STRn=3, QTRn=35; A4: STRn=8, QTRn=40; A7: STRn=7, QTRn=39; A9: STRn=6, QTRn=36; A10: STRn=6; QTRn=37). In our cohort, the reference allele A1 was the most frequent TCERG1 allele (96.9%). The frequencies of the other alleles were 0.2% (A2), 2.2% (A4), 0.4% (A7), 0.2% (A9), and 0.2% (A10). In the previously reported HD cohort, A1 (91.3%) and A2 (4.1%) were the most frequent alleles. None of our correlation analyses reached significance. However, mean AAO was 2.2 years later for the lower STR numbers and 1.9 years earlier for the higher STRs.

Conclusion: Likely due to the low heterogeneity of TCERG1 alleles in our cohort and a relatively small sample size, statistical analysis of the effect of the STR in TCERG1 on XDP AAO was not significant. Nonetheless, our data suggest that the length polymorphism in TCERG1 may be another common, albeit not very frequent, genetic modifier of AAO in HD and XDP.

References: [1] Lobanov, S. V. et al. Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1. npj Genom. Med. 7, 53 (2022).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/quasi-tandem-repeat-in-tcerg1-may-influence-age-at-onset-of-x-linked-dystonia-parkinsonism/