Response to Eura et al.

To the Editor: We appreciate Eura et al.1Eura M. Iida A. Ogasawara M. Hayashi S. Noguchi S. Nishino I. CGG repeat expansion in RILPL1 is absent in 159 individuals in Japanese cohort of oculopharyngodistal myopathy.2022Google Scholar for their interest in our recently published work. We read their letter, which demonstrated none of 159 Japanese individuals with ophthalmopharyngeal myopathy (OPDM) had abnormal CGG repeat expansion in the 5′ untranslated region (5′ UTR) of RILPL1 detected by RP-PCR, with great interest. The repeat sizes of all alleles detected by AL-PCR were within the range observed in unaffected controls. They concluded that the CGG repeat expansion in RILPL1 was rare in the Japanese cohort of individuals with OPDM.1Eura M. Iida A. Ogasawara M. Hayashi S. Noguchi S. Nishino I. CGG repeat expansion in RILPL1 is absent in 159 individuals in Japanese cohort of oculopharyngodistal myopathy.2022Google Scholar CGG repeat expansion in the 5′ UTR of RILPL1 was identified as the genetic cause of OPDM type 4 in 2022.2Yu J. Shan J. Yu M. Di L. Xie Z. Zhang W. Lv H. Meng L. Zheng Y. Zhao Y. et al.The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4.Am. J. Hum. Genet. 2022; 109: 533-541https://doi.org/10.1016/j.ajhg.2022.01.012Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar,3Zeng Y. Yang K. Du G. Chen Y. Cao C. Qiu Y. He J. Lv H. Qu Q. Chen J. et al.GGC Repeat Expansion of RILPL1 is Associated with Oculopharyngodistal Myopathy.Ann. Neurol. 2022; 92: 512-526https://doi.org/10.1002/ana.26436Crossref PubMed Scopus (6) Google Scholar In total, 11 out of 51 individuals with OPDM harbored this abnormal repeat expansion in our Chinese OPDM cohort.2Yu J. Shan J. Yu M. Di L. Xie Z. Zhang W. Lv H. Meng L. Zheng Y. Zhao Y. et al.The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4.Am. J. Hum. Genet. 2022; 109: 533-541https://doi.org/10.1016/j.ajhg.2022.01.012Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Subsequently, another independent Chinese group also identified CGG repeat expansion in RILPL1 in six individuals with OPDM from two families.3Zeng Y. Yang K. Du G. Chen Y. Cao C. Qiu Y. He J. Lv H. Qu Q. Chen J. et al.GGC Repeat Expansion of RILPL1 is Associated with Oculopharyngodistal Myopathy.Ann. Neurol. 2022; 92: 512-526https://doi.org/10.1002/ana.26436Crossref PubMed Scopus (6) Google Scholar A founder effect of the RILPL1 CGG expansion was identified in these two OPDM4-affected families by haplotype analysis.3Zeng Y. Yang K. Du G. Chen Y. Cao C. Qiu Y. He J. Lv H. Qu Q. Chen J. et al.GGC Repeat Expansion of RILPL1 is Associated with Oculopharyngodistal Myopathy.Ann. Neurol. 2022; 92: 512-526https://doi.org/10.1002/ana.26436Crossref PubMed Scopus (6) Google Scholar The founder effect has been identified in many repeat expansion diseases.4Depienne C. Mandel J.L. 30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?.Am. J. Hum. Genet. 2021; 108: 764-785https://doi.org/10.1016/j.ajhg.2021.03.011Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar The expanded allele associated with a single or predominant haplotype may lead to geographic clustering of the corresponding disease or high variability in different populations.4Depienne C. Mandel J.L. 30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?.Am. J. Hum. Genet. 2021; 108: 764-785https://doi.org/10.1016/j.ajhg.2021.03.011Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar As was reported, the hexanucleotide GGGGCC repeat expansion in C9orf72 was the most common genetic cause in clinically diagnosed amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European and North American populations while it was rare in East Asian population.4Depienne C. Mandel J.L. 30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?.Am. J. Hum. Genet. 2021; 108: 764-785https://doi.org/10.1016/j.ajhg.2021.03.011Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,5Balendra R. Isaacs A.M. C9orf72-mediated ALS and FTD: multiple pathways to disease.Nat. Rev. Neurol. 2018; 14: 544-558https://doi.org/10.1038/s41582-018-0047-2Crossref PubMed Scopus (306) Google Scholar Founder effect was also identified in pathogenic CGG repeat expansion in NOTCH2NLC in Japanese neuronal intranuclear inclusion disease (NIID)-affected individuals. Other NOTCH2NLC-related repeat expansion disorders, including essential tremor, Parkinson disease, and leukoencephalopathy, were very rare in the European population compared to the Asian population, suggesting the possibility of a founder effect in the Asian population. These findings were consistent with the genetic studies of different OPDM subtypes. (1) The OPDM1 caused by CGG repeat expansion in LRP12 was the dominant genetic cause among Japanese OPDM-affected individuals, while in China, the percentage of OPDM1 in genetically confirmed OPDM-affected individuals was less than 4.9%.2Yu J. Shan J. Yu M. Di L. Xie Z. Zhang W. Lv H. Meng L. Zheng Y. Zhao Y. et al.The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4.Am. J. Hum. Genet. 2022; 109: 533-541https://doi.org/10.1016/j.ajhg.2022.01.012Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar,6Yu J. Deng J. Wang Z. Oculopharyngodistal myopathy.Curr. Opin. Neurol. 2022; 35: 637-644https://doi.org/10.1097/wco.0000000000001089Crossref PubMed Google Scholar (2) The OPDM2 caused by CGG repeat expansion in GIPC1 was the most common OPDM subtype among Chinese OPDM-affected individuals, accounting for about 53.6% and 51.8% in two unrelated Chinese cohorts, respectively.2Yu J. Shan J. Yu M. Di L. Xie Z. Zhang W. Lv H. Meng L. Zheng Y. Zhao Y. et al.The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4.Am. J. Hum. Genet. 2022; 109: 533-541https://doi.org/10.1016/j.ajhg.2022.01.012Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar,6Yu J. Deng J. Wang Z. Oculopharyngodistal myopathy.Curr. Opin. Neurol. 2022; 35: 637-644https://doi.org/10.1097/wco.0000000000001089Crossref PubMed Google Scholar But it showed a very low proportion in Japan. (3) The OPDM4 caused by CGG repeat expansion in RILPL1 was the second most common subtype in our Chinese OPDM cohort,2Yu J. Shan J. Yu M. Di L. Xie Z. Zhang W. Lv H. Meng L. Zheng Y. Zhao Y. et al.The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4.Am. J. Hum. Genet. 2022; 109: 533-541https://doi.org/10.1016/j.ajhg.2022.01.012Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar whereas it was absent in the Japanese OPDM-affected individuals reported by Eura et al.1Eura M. Iida A. Ogasawara M. Hayashi S. Noguchi S. Nishino I. CGG repeat expansion in RILPL1 is absent in 159 individuals in Japanese cohort of oculopharyngodistal myopathy.2022Google Scholar Taken together, these findings indicated a different genetic architecture underlying OPDM in these populations, which may be attributed to the founder effect. The work was funded by the National Natural Science Foundation of China (nos. 81571219, 82071409, 82171846, 82160252, and U20A20356). The authors declare no competing interests. RILPL1-related OPDM is absent in a Japanese cohortEura et al.The American Journal of Human GeneticsNovember 03, 2022In BriefTo the Editor: We have read with great interest the recent article “The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4” by Yu et al.1 The authors identified the CGG repeat expansions in RILPL1 (MIM: 614092 ) in 11 unrelated individuals with oculopharyngodistal myopathy (OPDM) in China, which has become the fourth gene with a variant causative of OPDM after LRP12 (MIM: 618299 ), GIPC1 (MIM: 605072 ), and NOTCH2NLC (MIM: 618025 ).1,2,3,4,5 More recently, another group from China also reported on individuals with CGG expansion in RILPL1 in two families with OPDM. Full-Text PDF Open Archive