NIID NOTCH2NLC

Neuronal intranuclear inclusion disease (NIID) is a very rare multisystem neurodegenerative disorder characterized by the presence of eosinophilic intranuclear inclusions in neuronal and glial cells, and neuronal loss¹.

Prevalence

>400 patients reported in literature². Found in individuals of East Asian ancestry³.

Age of Onset Details

Typical: 30-70⁴; Range: 10⁵- 78⁶.

Locus

hg19

chr1:145209323-145209354

hg38

chr1:149390802-149390842

t2t

chr1:148519695-148519738

Details

Benign alleles are less than 38 repeats, while pathogenic alleles contain 66+ repeats⁷. Intermediate alleles may be associated with a phenotypic spectrum, and even pathogenic cases can have variable phenotype^8,9: NOTCH2NLC expansions have been linked Alzheimer's disease and Parkinson's disease, leading to a potential role in NIID-related disorders¹⁰. Age of onset inversely related to allele size¹¹. Motif variation in controls: (AGG)(CGG)n(AGG)0-3(CGG)0-2. GGA and AGC interruptions may influence phenotype¹². Interruptions documented: GGA, GGG¹³; ACCGAGAAGATGCCCGCCCTGC interruption proposed but not confirmed¹⁴. Detection may be challenging due to parology between genes: C253572.1, NOTCH2, NOTCH2NL, NBPF14, NBPF19.

Mechanism

GoF

Polyglycine expansion; may relate to methylation or RNA pathogenicity^4,15,14. The polyglycine-containing protein sequesters a key subunit of transcription factor NF-κB in nuclear inclusions, leading to impaired autophagy¹⁶.

Year

2019¹⁷

Location in Gene

5' UTR

Gene Strand

Alleles

Ref. Motif

GGC

Pathogenic (ref.)

GGC

Pathogenic (gene)

CGG

gnomAD

Pathogenic genotype frequency data is not displayed for this locus because a substantial number of large alleles failed manual review by the gnomAD team.

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0011327

Heterogenous Genetic, Clinical, and Imaging Features in Patients with Neuronal Intranuclear Inclusion Disease Carrying

Yusran Ady,Fitrah, Yo,Higuchi, Norikazu,Hara, Takayoshi,Tokutake, Masato,Kanazawa, Kazuhiro,Sanpei, Tomone,Taneda, Akihiko,Nakajima, Shin,Koide, Shintaro,Tsuboguchi, Midori,Watanabe, Junki,Fukumoto, Shoichiro,Ando, Tomoe,Sato, Yohei,Iwafuchi, Aki,Sato, Hideki,Hayashi, Takanobu,Ishiguro, Hayato,Takeda, Toshiaki,Takahashi, Nobuyoshi,Fukuhara, Kensaku,Kasuga, Akinori,Miyashita, Osamu,Onodera, Takeshi,Ikeuchi

Brain sciences · 2023-06-15

pmid:37371433

Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis.

Elisa,Vegezzi, Hiroyuki,Ishiura, D Cristopher,Bragg, David,Pellerin, Francesca,Magrinelli, Riccardo,Currò, Stefano,Facchini, Arianna,Tucci, John,Hardy, Nutan,Sharma, Matt C,Danzi, Stephan,Zuchner, Bernard,Brais, Mary M,Reilly, Shoji,Tsuji, Henry,Houlden, Andrea,Cortese

The Lancet. Neurology · 2024-07-01

pmid:38876750

omim:603472

Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease.

Hongfei,Tai, An,Wang, Yumei,Zhang, Shaocheng,Liu, Yunzhu,Pan, Kai,Li, Guixian,Zhao, Mengwen,Wang, Guode,Wu, Songtao,Niu, Hua,Pan, Bin,Chen, Wei,Li, Xingao,Wang, Gehong,Dong, Wei,Li, Ying,Zhang, Sheng,Guo, Xiaoyun,Liu, Mingxia,Li, Hui,Liang, Ming,Huang, Wei'an,Chen, Zaiqiang,Zhang

Neurology. Genetics · 2023-02-28

pmid:37090934

Rapidly progressive adult-onset neuronal intranuclear inclusion disease beginning with autonomic symptoms: a case report.

Yi,Zhu, Qian,Yang, Yun,Tian, Weibing,Fan, Xinfa,Mao

Frontiers in neurology · 2023-05-25

pmid:37305750

Resources for Genetics Professionals — Genetic Disorders Caused by Nucleotide Repeat Expansions and Contractions

Stephanie E.,Wallace, Lora JH,Bean

GeneReviews® [Internet] · 2022-10-20

genereviews:NBK535148

Erratum: Prevalence and Characterization of

Neurology. Genetics · 2024-07-12

pmid:39055960

Familial adult-onset neuronal intranuclear inclusion disease: A case report and literature review.

Lijun,Wei, Jiaqi,Wang, Changming,Xu, Tengchao,Yang, Yun,Tian, Lu,Shen

Medicine · 2024-11-01

pmid:39496005

Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders.

Yun,Tian, Jun-Ling,Wang, Wen,Huang, Sheng,Zeng, Bin,Jiao, Zhen,Liu, Zhao,Chen, Yujing,Li, Ying,Wang, Hao-Xuan,Min, Xue-Jing,Wang, Yong,You, Ru-Xu,Zhang, Xiao-Yu,Chen, Fang,Yi, Ya-Fang,Zhou, Hong-Yu,Long, Chao-Jun,Zhou, Xuan,Hou, Jun-Pu,Wang, Bin,Xie, Fan,Liang, Zhuan-Yi,Yang, Qi-Ying,Sun, Emily G,Allen, Andrew Mark,Shafik, Ha Eun,Kong, Ji-Feng,Guo, Xin-Xiang,Yan, Zheng-Mao,Hu, Kun,Xia, Hong,Jiang, Hong-Wei,Xu, Ran-Hui,Duan, Peng,Jin, Bei-Sha,Tang, Lu,Shen

American journal of human genetics · 2019-06-06

pmid:31178126

Neuronal Intranuclear Inclusion Disease with NOTCH2NLC GGC Repeat Expansion: A Systematic Review and Challenges of Phenotypic Characterization.

Tian,Zeng, Yiqun,Chen, Honghao,Huang, Shengqi,Li, Jiaqi,Huang, Haobo,Xie, Shenyi,Lin, Siyao,Chen, Guangyong,Chen, Dehao,Yang

Aging and disease · 2024-02-16

pmid:38377026

The Phenotypes and Mechanisms of NOTCH2NLC-Related GGC Repeat Expansion Disorders: a Comprehensive Review.

Xiu-Rong,Huang, Bei-Sha,Tang, Peng,Jin, Ji-Feng,Guo

Molecular neurobiology · 2021-10-31

pmid:34718964

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing.

Igor,Stevanovski, Sanjog R,Chintalaphani, Hasindu,Gamaarachchi, James M,Ferguson, Sandy S,Pineda, Carolin K,Scriba, Michel,Tchan, Victor,Fung, Karl,Ng, Andrea,Cortese, Henry,Houlden, Carol,Dobson-Stone, Lauren,Fitzpatrick, Glenda,Halliday, Gianina,Ravenscroft, Mark R,Davis, Nigel G,Laing, Avi,Fellner, Marina,Kennerson, Kishore R,Kumar, Ira W,Deveson

Science advances · 2022-03-04

pmid:35245110

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784

Clinical and neuroimaging review of triplet repeat diseases.

Ryo,Kurokawa, Mariko,Kurokawa, Akihiko,Mitsutake, Moto,Nakaya, Akira,Baba, Yasuhiro,Nakata, Toshio,Moritani, Osamu,Abe

Japanese journal of radiology · 2022-09-28

pmid:36169768

uN2CpolyG-mediated p65 nuclear sequestration suppresses the NF-κB-NLRP3 pathway in neuronal intranuclear inclusion disease

Yu,Shen, Kaiyan,Jiang, Dandan,Tan, Min,Zhu, Yusen,Qiu, Pencheng,Huang, Wenquan,Zou, Jianwen,Deng, Zhaoxia,Wang, Ying,Xiong, Daojun,Hong

Cell Communication and Signaling · 2025-02-07

doi:10.1186/s12964-025-02079-1

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

Hiroyuki,Ishiura, Shota,Shibata, Jun,Yoshimura, Yuta,Suzuki, Wei,Qu, Koichiro,Doi, M Asem,Almansour, Junko Kanda,Kikuchi, Makiko,Taira, Jun,Mitsui, Yuji,Takahashi, Yaeko,Ichikawa, Tatsuo,Mano, Atsushi,Iwata, Yasuo,Harigaya, Miho Kawabe,Matsukawa, Takashi,Matsukawa, Masaki,Tanaka, Yuichiro,Shirota, Ryo,Ohtomo, Hisatomo,Kowa, Hidetoshi,Date, Aki,Mitsue, Hiroyuki,Hatsuta, Satoru,Morimoto, Shigeo,Murayama, Yasushi,Shiio, Yuko,Saito, Akihiko,Mitsutake, Mizuho,Kawai, Takuya,Sasaki, Yusuke,Sugiyama, Masashi,Hamada, Gaku,Ohtomo, Yasuo,Terao, Yoshihiko,Nakazato, Akitoshi,Takeda, Yoshio,Sakiyama, Yumi,Umeda-Kameyama, Jun,Shinmi, Katsuhisa,Ogata, Yutaka,Kohno, Shen-Yang,Lim, Ai Huey,Tan, Jun,Shimizu, Jun,Goto, Ichizo,Nishino, Tatsushi,Toda, Shinichi,Morishita, Shoji,Tsuji

Nature genetics · 2019-07-22

pmid:31332380

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Type B Fibers: A Novel Ultrastructural Biomarker for Cognitive Impairment in Neuronal Intranuclear Inclusion Disease.

Binbin,Zhou, Shaoping,Zhong, Yangye,Lian, Jingzhen,Liang, Luyao,Huang, Jing,Ding, Xin,Wang

Brain sciences · 2025-09-23

pmid:41154122

Association of Non-Coding Repeat Expansions with Parkinson's Disease Risk: Evidence from a UK Biobank-Based Whole-Genome Sequencing Study.

Zhen,Hu, Qin-Qin,Yan, Jing-Jin,Wan, Yu,Fan, Jun,Liu

Movement disorders : official journal of the Movement Disorder Society · 2025-10-11

pmid:41074692

Dual diagnosis at the neuro-immune interface: a case report of neuronal intranuclear inclusion disease with acute anti-CASPR2 encephalitis.

Wan,Zhu, Tiansi,Liu, Xinran,Yu, Min,Peng, Jinghan,Hu

Frontiers in immunology · 2025-08-26

pmid:40934004

Prevalence of NOTCH2NLC and FMR1 Repeat Expansions in Atypical Parkinsonism Compared to Asymptomatic Elderly Individuals.

Pin-Shiuan,Chen, Yi-Ling,Liu, Pu-Tien,Chiang, Hsin-Hsi,Tsai, Ming-Jen,Lee, Yang-Yee,Chang, Min-Yu,Lan, Yih-Ru,Wu, Ing-Tsung,Hsiao, Cheng-Hsuan,Li, Sung-Pin,Fan, Chun-Hwei,Tai, Han-Lin,Chiang, Chun-Yu,Chen, Tsung-Lin,Lee, Koping,Chang, Chin-Song,Lu, Hsiu-Chen,Chang, Yi-Syuan,Ke, Yen-Chen Anne,Feng, Jacob Shujui,Hsu, Chin-Hsien,Lin

Movement disorders : official journal of the Movement Disorder Society · 2025-07-15

pmid:40879637

Non-coding repeat analyses in patients with Parkinson's disease.

Makito,Hirano, Makoto,Samukawa, Satoko,Miyatake, Yuko,Yamagishi, Chiharu,Isono, Rino,Yoshikawa, Kazumasa,Saigoh, Atsushi,Terayama, Yuji,Higashimoto, Eriko,Koshimizu, Takeshi,Mizuguchi, Kanako,Fujii, Yoshiyuki,Mitsui, Naomichi,Matsumoto, Yoshitaka,Nagai

Frontiers in neurology · 2025-07-22

pmid:40765612

NOTCH2NLC Repeat Expansions in Parkinsonian Disorders: Clinical and Neuroimaging Characteristics.

Han-Lin,Chiang, Kang-Yang,Jih, Cheng-Tsung,Hsiao, Fu-Pang,Chang, Justus Chunyu,Chen, Yi-Chu,Liao, Yih-Ru,Wu, Yi-Chung,Lee

Annals of clinical and translational neurology · 2025-07-24

pmid:40708231

CGG repeat expansions in Charcot-Marie-Tooth disease: insights from the 100 000 Genomes Project.

Alessandro,Bertini, Stefano,Facchini, Ilaria,Quartesan, Riccardo,Currò, Ricardo Parolin,Schnekenberg, Natalia,Dominik, Gustavo,Alves, Lucia,Ferullo, Arianna,Tucci, Henry,Houlden, Mary M,Reilly, Andrea,Cortese

Journal of neurology, neurosurgery, and psychiatry · 2025-07-11

pmid:40645757

Diverse Clinical Phenotypes of Neuronal Intranuclear Inclusion Disease in South Korea.

Min Young,Chun, Sang Won,Seo, Hyemin,Jang, Duk L,Na, Seongmi,Kim, Na Kyung,Lee, Seung-Yeon,Lee, Kyung Bok,Lee, Jinyoung,Youn, Ja-Hyun,Jang, Na-Yeon,Jung, Eun Hye,Lee, Jee Hyang,Jeong, Soo Jin,Yoon, Hyung Chan,Kim, Joonwon,Lee, Seongho,Park, Jinse,Park, Heejeong,Jeong, Tae-Won,Yang, Eungseok,Oh, Eun-Joo,Kim, Jiyoung,Kim, Ji Eun,Lee, Ji-Yun,Park, Takeshi,Mizuguchi, Shinichi,Kameyama, Naomichi,Matsumoto, Yeon-Lim,Suh, Hee Jin,Kim

Journal of clinical neurology (Seoul, Korea) · 2025-07-01

pmid:40635536

Generation of an induced pluripotent stem cell line (HZSMHCi002-A) from a patient with neuronal intranuclear inclusion disease carrying GGC repeat expansion in the NOTCH2NLC gene.

Xinyi,Ren, Chuqing,Zhou, Youhui,Jiang, Jun,Zhao, Xiaoyi,Tina, Naxin,Xu, Mengshan,Fu, Peiyan,Ni, Tao,Li, Xiaoying,Zhang

Stem cell research · 2025-06-28

pmid:40609325