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Long-read sequencing identified repeat expansions in the 5'UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease.
J Med Genet. 2019 11; 56(11):758-764.JM

Abstract

BACKGROUND

Neuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5'-untranslated region (5'UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients.

METHODS

Fifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases.

RESULTS

Our patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5'UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases.

CONCLUSION

Our findings provided evidence that confirmed the GGC repeated expansion in the 5'UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.

Authors+Show Affiliations

Department of Neurology, Peking University First Hospital, Beijing, China.Department of Neurology, Peking University First Hospital, Beijing, China.GrandOmics Biosciences, Beijing, China.Department of Neurology, Sixth Medical Center of PLA General Hospital, Beijing, China.Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, China.Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, China.Department of Neurology, Bethune First Affiliated Hospital of Jilin University, Nanchang, China.GrandOmics Biosciences, Beijing, China.GrandOmics Biosciences, Beijing, China.GrandOmics Biosciences, Beijing, China.Department of Neurology, Peking University People's Hospital, Beijing, China.Department of Neurology, Peking University First Hospital, Beijing, China.Department of Neurology, Peking University First Hospital, Beijing, China.Department of Neurology, Peking University First Hospital, Beijing, China.Department of Neurology, Peking University First Hospital, Beijing, China.Department of Neurology, Peking University First Hospital, Beijing, China.Department of Neurology, Peking University First Hospital, Beijing, China.Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, China hongdaojun@hotmail.com drwangzx@163.com. Department of Neurology, Peking University People's Hospital, Beijing, China.Department of Neurology, Peking University First Hospital, Beijing, China hongdaojun@hotmail.com drwangzx@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31413119

Citation

Deng, Jianwen, et al. "Long-read Sequencing Identified Repeat Expansions in the 5'UTR of the NOTCH2NLC Gene From Chinese Patients With Neuronal Intranuclear Inclusion Disease." Journal of Medical Genetics, vol. 56, no. 11, 2019, pp. 758-764.
Deng J, Gu M, Miao Y, et al. Long-read sequencing identified repeat expansions in the 5'UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease. J Med Genet. 2019;56(11):758-764.
Deng, J., Gu, M., Miao, Y., Yao, S., Zhu, M., Fang, P., Yu, X., Li, P., Su, Y., Huang, J., Zhang, J., Yu, J., Li, F., Bai, J., Sun, W., Huang, Y., Yuan, Y., Hong, D., & Wang, Z. (2019). Long-read sequencing identified repeat expansions in the 5'UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease. Journal of Medical Genetics, 56(11), 758-764. https://doi.org/10.1136/jmedgenet-2019-106268
Deng J, et al. Long-read Sequencing Identified Repeat Expansions in the 5'UTR of the NOTCH2NLC Gene From Chinese Patients With Neuronal Intranuclear Inclusion Disease. J Med Genet. 2019;56(11):758-764. PubMed PMID: 31413119.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-read sequencing identified repeat expansions in the 5'UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease. AU - Deng,Jianwen, AU - Gu,Muliang, AU - Miao,Yu, AU - Yao,Sheng, AU - Zhu,Min, AU - Fang,Pu, AU - Yu,Xuefan, AU - Li,Pidong, AU - Su,Yanan, AU - Huang,Jian, AU - Zhang,Jun, AU - Yu,Jiaxi, AU - Li,Fan, AU - Bai,Jing, AU - Sun,Wei, AU - Huang,Yining, AU - Yuan,Yun, AU - Hong,Daojun, AU - Wang,Zhaoxia, Y1 - 2019/08/14/ PY - 2019/05/06/received PY - 2019/06/25/revised PY - 2019/07/16/accepted PY - 2019/8/16/pubmed PY - 2020/6/18/medline PY - 2019/8/16/entrez KW - GGC repeated expansion KW - NIID KW - NOTCH2NLC KW - genetics KW - neurology SP - 758 EP - 764 JF - Journal of medical genetics JO - J Med Genet VL - 56 IS - 11 N2 - BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5'-untranslated region (5'UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients. METHODS: Fifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases. RESULTS: Our patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5'UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases. CONCLUSION: Our findings provided evidence that confirmed the GGC repeated expansion in the 5'UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients. SN - 1468-6244 UR - https://www.unboundmedicine.com/medline/citation/31413119/Long_read_sequencing_identified_repeat_expansions_in_the_5'UTR_of_the_NOTCH2NLC_gene_from_Chinese_patients_with_neuronal_intranuclear_inclusion_disease_ L2 - https://jmg.bmj.com/lookup/pmidlookup?view=long&pmid=31413119 DB - PRIME DP - Unbound Medicine ER -