Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.

Authors: Sone, Jun and Mitsuhashi, Satomi and Fujita, Atsushi and Mizuguchi, Takeshi and Hamanaka, Kohei and Mori, Keiko and Koike, Haruki and Hashiguchi, Akihiro and Takashima, Hiroshi and Sugiyama, Hiroshi and Kohno, Yutaka and Takiyama, Yoshihisa and Maeda, Kengo and Doi, Hiroshi and Koyano, Shigeru and Takeuchi, Hideyuki and Kawamoto, Michi and Kohara, Nobuo and Ando, Tetsuo and Ieda, Toshiaki and Kita, Yasushi and Kokubun, Norito and Tsuboi, Yoshio and Katoh, Kazutaka and Kino, Yoshihiro and Katsuno, Masahisa and Iwasaki, Yasushi and Yoshida, Mari and Tanaka, Fumiaki and Suzuki, Ikuo K and Frith, Martin C and Matsumoto, Naomichi and Sobue, Gen

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 difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. 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.

Journal: Nature genetics
DOI: 10.1038/s41588-019-0459-y
Year: 2019

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