The role of genetics in neurodegenerative dementia: a large cohort study in South China

Bin Jiao,Yaling Jiang,Jinchen Li,Yuan Zhu,Xin Wang,Lu Shen,Yafang Zhou,Lu Zhou,Beisha Tang,Weiwei Zhang,Lina Guo,Lin Zhou,Junling Wang,Xuewen Xiao,Hui Liu,Ling Weng,Xinxin Liao,Qijie Yang,Xinxiang Yan

doi:10.1038/s41525-021-00235-3

Abstract

Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and complicated etiology. There exist potential genetic component overlaps between different neurodegenerative dementias. Here, 1795 patients with neurodegenerative dementias from South China were enrolled, including 1592 with Alzheimer’s disease (AD), 110 with frontotemporal dementia (FTD), and 93 with dementia with Lewy bodies (DLB). Genes targeted sequencing analysis were performed. According to the American College of Medical Genetics (ACMG) guidelines, 39 pathogenic/likely pathogenic (P/LP) variants were identified in 47 unrelated patients in 14 different genes, including PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, SIGMAR1, and abnormal repeat expansions in C9orf72 and HTT. Overall, 33.3% (13/39) of the variants were novel, the identified P/LP variants were seen in 2.2% (35/1592) and 10.9% (12/110) of AD and FTD cases, respectively. The overall molecular diagnostic rate was 2.6%. Among them, PSEN1 was the most frequently mutated gene (46.8%, 22/47), followed by PSEN2 and APP. Additionally, the age at onset of patients with P/LP variants (51.4 years), ranging from 30 to 83 years, was ~10 years earlier than those without P/LP variants (p < 0.05). This study sheds insight into the genetic spectrum and clinical manifestations of neurodegenerative dementias in South China, further expands the existing repertoire of P/LP variants involved in known dementia-associated genes. It provides a new perspective for basic research on genetic pathogenesis and novel guiding for clinical practice of neurodegenerative dementia.

Highlights

Neurodegenerative dementias are a group of clinically heterogeneous diseases with frequently overlapping symptoms, such as multi-cognitive impairments, behavioral changes, and movement deficits[1]
All identified pathogenic/likely pathogenic (P/LP) variants were responsible for 2.2% of Alzheimer’s disease (AD) (35/1592) and 10.9% of Frontotemporal dementia (FTD) (12/110), which led to an overall molecular diagnostic yield of 2.6% (Fig. 1), in this study, no P/LP variants were identified in dementia with Lewy bodies (DLB) patients. 70.2% (33/47) of patients had a positive family history and 46.8% (22/47) of patients with P/LP variants had at least one APOE4
We determined the mutational spectrum of 36 known dementia-associated genes in patients clinically diagnosed with neurodegenerative dementia patients, including AD, FTD, and DLB in a South China population sample using integrated targeted gene sequencing analysis

Summary

Introduction

Neurodegenerative dementias are a group of clinically heterogeneous diseases with frequently overlapping symptoms, such as multi-cognitive impairments, behavioral changes, and movement deficits[1]. Frontotemporal dementia (FTD) is the second most common cause of neurodegenerative dementia after AD in patients younger than 65 years, responsible for 10.2% of cases[3], and dementia with Lewy bodies (DLB) has been reported as being the second most common dementia subtype in older people following AD, accounting for 7.5% of all dementia cases[4]. The etiology of neurodegenerative dementias is still obscure, which is thought to be caused by a combination of ageing, environmental, and genetic factors. PSEN1, PSEN2, and APP are recognized as three causative genes for familial AD (FAD), which explains the genetic background of 5–10% of early onset AD (EOAD, younger than 65 years). FTD is a genetically and pathologically heterogeneous disorder with a higher incidence of familial cases than AD. Growing evidence supports that DLB has a strong and unique genetic component[9]

Methods

Results

Conclusion