Identify the cause of Neuronal intranuclear inclusion disease (NIID).

  Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central, peripheral and autonomic nervous system cells, and also in visceral organs cells. NIID cases have been reported after post-mortem examination. In 2003, the review of NIID described that the onset of disease varies from infancy to the sixties, but two-thirds of them were infantile or juvenile, and very wide range of clinical manifestations has been reported. This makes ante-mortem diagnosis of NIID difficult. In 2011, we reported the usefulness of skin biopsy. Then, the number of NIID cases has increased.

We study  the genome of NIID with from two familial NIID cases diagnosed by autopsy and skin biopsy. We studied linkage analysis with micro-satellite markers, and then sequence with short-read NGS to examine SNV, and analyzed linkage analysis again. Finally we studied long-read NGS with Nanopore MinION and Pacbio RS II.

We studied linkage analysis with micro-satellite markers and identified a peak showing highest LOD score 4.82 at 1p31.1-1q21.3. Next, we studied with short-read NGS, but we could not find any nonsynonymous variations that segregate with NIID. We need  to include more familial NIID patients, and find that skin biopsy was useful. We studied linkage analysis again with SNV data, and found highest LOD score 4.21 in almost same position of the result with micro-satellite markers. We promoted long-read NGS study including newly diagnosed NIID cases with skin biopsy, 9 families, and 40 sporadic NIID patients. We identified a GGC repeat expansion in NOTCH2NLC in all and only affected NIID patients. 

We can now diagnose NIID more precisely with clinical, pathological and genetical means. We will promote molecular biological study and radical treatment of NIID.