Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1,2,3,4,5,6,7,8, but skin biopsy enables its ante-mortem diagnosis9,10,11,12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1–q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5′ region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.
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Long-read sequencing data have been deposited in the Human Genetic Variation Database under accession ID: HGV0000008.
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The authors thank all of the patients and their families for participating in this study.
The authors also thank O. Komure, N. Kitagawa, H. Yoshimura, J. Ishii, K. Higashida, M. Togo, T. Yuasa, H. Nakayasu, Y. Suto, T. Manabe, M. Takahashi, M. Tsutiya, N. Uehara, H. Mori, T. Tokunaga, T. Inuzuka, A. Takekoshi, S. Anzai, K. Kondo, T. Takahashi, K. Muguruma, Y. Sugihara, K. Yokote, S. Takamura, N. Oohara, E. Hayano, K. Saiki, D. Hori, Y. Izumi, R. Kobayashi, M. Saiki, Y. Tsukahara, M. Kuriyama, T. Kurashige, Y. Takahashi, T. Noda, S. Takagi, K. Honda, H. Kishida, M. Ito, A. Yarita, Y. Satake, T. Inagaki, K. Hiraga, Y. Kato and many neurologists for clinical evaluation of patients with NIID and for providing support with the diagnosis of patients with NIID. This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18kk0205001, JP18ek0109348, JP18md0107059, JP18ek0109284, JP18dm020715, JP18dm0107059 and JP18am0101108; the Japan Society for the Promotion of Science (JSPS) KAKENHI grant numbers JP19659225, JP17K15639, JP17K16132, JP17K15630, JP17H06994, JP24591257, JP15K09312 and JP16K07464; MEXT Grant-in Aid Project under grant numbers 26119002 and 26117002; the Takeda Science Foundation; the Daiwa Securities Health Foundation; and the Termo Foundation for Life Sciences and Arts.
The authors declare no competing interests.
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