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

Yun Tian,Ying Wang,Fang Yi,Yujing Li,Bin Jiao,Ha Eun Kong,Fan Liang,Emily G Allen,Peng Jin,Xuan Hou,Kun Xia,Zhen Liu,Sheng Zeng,Zhao Chen,Wen Huang,Lu Shen,Yong You,Hong Jiang,Hongwei Xu ,Junpu Wang ,Andrew M Shafik ,Ranhui Duan ,Yifei Zhou ,Baohua Xie ,Beisha Tang ,Xiaoyu Chen ,Hongyu Long ,Zhengmao Hu ,Zhiyong Yang ,Jifeng Guo ,Ruxu Zhang ,Junling Wang ,Xuejing Wang ,Xinxiang Yan ,Haoxuan Min ,Chaojun Zhou ,Qiying Sun

doi:10.1016/j.ajhg.2019.05.013

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.

Highlights

IntroductionNeuronal intranuclear inclusion disease (NIID [MIM: 603472]) is a rare multisystem neurodegenerative disease characterized by the pathology of eosinophilic intranuclear inclusions in the central, peripheral, and autonomic nervous systems, as well as in the visceral organs.[1,2] The first NIID-affected case subject was reported in 1968.3 until 2011, only about 40 NIID-affected case subjects had been described worldwide, which were diagnosed by post-mortem brain biopsy.[1,4,5,6,7,8,9,10,11,12,13] Because eosinophilic intranuclear inclusions exist in dermal cells of NIIDaffected individuals,[14,15] skin biopsy has become a useful tool to confirm NIID diagnosis, and the number of reported cases has increased to more than 100 case subjects.[2]Both familial and sporadic case subjects have been described.[2]
NOTCH2NLA, B, and C are highly similar to each other, with more than 98% sequence identity over NOTCH2NL exons 1–5.30 only NOTCH2NLC contains the GGC repeat in the reference human genome, (GGC)9(GGA)2(GGC)[2], which is expanded in the Neuronal intranuclear inclusion disease (NIID)-affected family that we have examined here (Figures 1D and 1E)
Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs

Summary

Introduction

Neuronal intranuclear inclusion disease (NIID [MIM: 603472]) is a rare multisystem neurodegenerative disease characterized by the pathology of eosinophilic intranuclear inclusions in the central, peripheral, and autonomic nervous systems, as well as in the visceral organs.[1,2] The first NIID-affected case subject was reported in 1968.3 until 2011, only about 40 NIID-affected case subjects had been described worldwide, which were diagnosed by post-mortem brain biopsy.[1,4,5,6,7,8,9,10,11,12,13] Because eosinophilic intranuclear inclusions exist in dermal cells of NIIDaffected individuals,[14,15] skin biopsy has become a useful tool to confirm NIID diagnosis, and the number of reported cases has increased to more than 100 case subjects.[2]Both familial and sporadic case subjects have been described.[2]. Neuronal intranuclear inclusion disease (NIID [MIM: 603472]) is a rare multisystem neurodegenerative disease characterized by the pathology of eosinophilic intranuclear inclusions in the central, peripheral, and autonomic nervous systems, as well as in the visceral organs.[1,2] The first NIID-affected case subject was reported in 1968.3 until 2011, only about 40 NIID-affected case subjects had been described worldwide, which were diagnosed by post-mortem brain biopsy.[1,4,5,6,7,8,9,10,11,12,13] Because eosinophilic intranuclear inclusions exist in dermal cells of NIIDaffected individuals,[14,15] skin biopsy has become a useful tool to confirm NIID diagnosis, and the number of reported cases has increased to more than 100 case subjects.[2]. The typical symmetrical high signal seen in corticomedullary junctions using diffusion weighted imaging (DWI) could be a powerful tool for screening NIID-affected case

Methods

Results

Conclusion