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

• Authors: Yun Tian, Central South University; Jun-Ling Wang, Central South University; Wen Huang, Central South University; Sheng Zeng, Central South University; Bin Jiao, Central South University; Zhen Liu, Central South University; Zhao Chen, Central South University; Yujing Li, Emory University; Ying Wang, Central South University; Hao-Xuan Min, GrandOm Biosciences; Xue-Jing Wang, Zhengzhou University; Yong You, University of South China; Ru-Xu Zhang, Central South University; Xiao-Yu Chen, Central South University; Fang Yi, Central South University; Ya-Fang Zhou, Central South University; Hong-Yu Long, Central South University; Chao-Jun Zhou, Central South University; Emily Graves Allen, Emory University; Peng Jin, Emory University
• Journal Title: American Journal of Human Genetics
• Volume: Volume 105, Number 1
• Publisher: Elsevier (Cell Press): 6 month embargo | 2019-07-03, Pages 166-176
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.ajhg.2019.05.013
• Subjects: Biology, Genetics; Biology, Neuroscience
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; MULTIPLE SYSTEM ATROPHY; FRAGILE-X; TRINUCLEOTIDE REPEAT; BODY DISEASE; HEXANUCLEOTIDE REPEAT; HYALINE INCLUSIONS; CAG TRINUCLEOTIDE; GENE; REGION; POLYGLUTAMINE

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.