Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease


Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

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Fig. 1: Brain MRI of patients with FXTAS, NIID, OPML and OPDM.
Fig. 2: Direct identification of repeat expansion mutations by analysis of short reads of whole-genome sequence data.
Fig. 3: Identification of CGG repeat expansion mutations in NBPF19 in NIID.
Fig. 4: Characterization of CGG repeat expansion mutations in the 5′ UTR of NBPF19 in patients with NIID.
Fig. 5: Identification of CGG repeat expansions in LOC642361/NUTM2B-AS1 in a family with OPML.
Fig. 6: Identification of CGG repeat expansions in LRP12 in families with OPDM.

Data availability

The genotyping microarray data and sequence data obtained by massively parallel sequencing analysis, including whole-genome sequencing and transcriptome analyses, are available on request from the corresponding author. Since whole-genome sequence data are protected by the Personal Information Protection Law, these data are available under regulation by the institutional review board.


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We thank the patients and family members for participating in the study. We also thank the neurologists, pathologists and radiologists of the patients for collecting and providing clinical information, K. J. L. Porto for proofreading, and K. Hirayama, M. Takeyama, Z. Wu and K. Wakabayashi for technical support. This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas (numbers 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grants-in-Aid (H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080) from the Ministry of Health, Labour and Welfare, Japan, and grants (numbers 15ek0108065h0002, 16kk0205001h0001, 17kk0205001h0002 and 17ek0109279h0001) from the Japan Agency for Medical Research and Development; all to S.T.). This work was also supported by KAKENHI (Grants-in-Aid for Young Scientists (numbers 15K20941 and 17H05085) from the Japan Society for the Promotion of Science; to H.I) and the Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation (GRIFIN) from the Japan Agency for Medical Research and Development (to S. Morishita).

Author information

H.I. and S.T. designed the research. H.I., S.S., M.A.A., J.K., M.Taira, J.M., Y.Takahashi, Y.I., T.Matsukawa, M.Tanaka, H.D., J.G., T.T. and S.T. performed the experiments and/or analyzed the data. H.I., S.S., J.Y., Y.Suzuki., W.Q., K.D. and S.Morishita performed the computational analysis. H.I., S.S., J.K., M.Taira, J.M., Y.Takahashi, Y.I., T.Mano, A.I., Y.H., M.K.M., T.Matsukawa, M.Tanaka, Y.Shirota, R.O., H.K., A.Mitsue., H.H., S.Morimoto, S.Murayama, Y.Shiio, Y.Saito, A.Mitsutake, M.K., T.S., Y.Sugiyama, M.H., G.O., Y.Terao, Y.N., A.T., Y.Sakiyama, Y.U.-K., J.Shinmi, K.O., Y.K., S.-Y.L., A.H.T., J.Shimizu, J.G., I.N., T.T. and S.T. collected and analyzed the clinical data and/or provided patients’ samples. H.I. and S.T. wrote the manuscript, together with contributions from S.S. and S.Morishita. All authors contributed to and critically reviewed the manuscript.

Correspondence to Shoji Tsuji.

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