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Am J Hum Genet. 2019 Jul 3;105(1):166-176. doi: 10.1016/j.ajhg.2019.05.013. Epub 2019 Jun 6.

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

Author information

1
Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
2
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
3
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China.
4
Department of Human Genetics, Emory University School of Medicine, Whitehead Research Building, Room 305A, 615 Michael Street, Atlanta, GA 30322, USA.
5
Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
6
GrandOmics Biosciences, Beijing 100000, China.
7
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
8
Department of Neurology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421000, China.
9
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
10
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
11
Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
12
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410008, China.
13
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, China.
14
Department of Human Genetics, Emory University School of Medicine, Whitehead Research Building, Room 305A, 615 Michael Street, Atlanta, GA 30322, USA. Electronic address: peng.jin@emory.edu.
15
Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
16
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: shenlu@csu.edu.cn.

Abstract

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.

KEYWORDS:

GGC repeat expansions; NOTCH2NLC; linkage analysis; long-read genome sequencing; neuronal intranuclear inclusion disease; whole-exome sequencing

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