Genetic Screening of Patients with Sporadic Alzheimer’s Disease and Frontotemporal Lobar Degeneration in the Chinese Population

Article type: Research Article

Authors: Li, Yaoru^{a; b; 1} | Yang, Ziying^{c; d; 1} | Zhang, Yanxin^a | Liu, Fang^a | Xu, Jing^a | Meng, Yaping^a | Xing, Gebeili^a | Ruan, Xuqin^d | Sun, Jun^d | Zhang, Nan^{a; *}

Affiliations: [a] Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Heping District, Tianjin, China | [b] Department Five of Neurology, Cangzhou Central Hospital, Yunhe District, Cangzhou, Hebei, China | [c] College of Life Sciences, University of Chinese Academy of Sciences, Shijingshan District, Beijing, China | [d] Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, China

Correspondence: [*] Correspondence to: Nan Zhang, MD, PhD, Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 154, Anshan Road, Heping District, Tianjin 300052, China. Tel.: +8622 60814622; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective:This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods:A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results:Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions:There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases.

Keywords: Alzheimer’s disease, frontotemporal lobar degeneration, variant, whole-exome sequencing

DOI: 10.3233/JAD-231361

Journal: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 577-593, 2024