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

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.

Genetic Spectrum and Clinical Heterogeneity of Chinese Frontotemporal Dementia Patients: Data from PUMCH Dementia Cohort

“…These is close to the previous findings. In a Chinese south cohort, 10.9% FTD patients harbored a pathogenic/likely pathogenic variant [ 16 ]. Moreover, we find that svPPA and nvPPA patients have higher mutation frequencies than bvFTD patients (22.0%, 19.0% versus 6.1%).…”

Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease

“…Further review of the literature reveals that HTRA1 is capable of degrading APP and APOE in addition to tau [ 241 , 242 ]. This suggests that rare, deleterious variation within HTRA1 might increase EOAD risk (as suggested in [ 225 ]) not only via mechanisms related to CARASIL/CADASIL (i.e., in a manner analogous to NOTCH3 pathogenic variants), but also potentially via effects on tau, APP, or APOE metabolism. Querying the full STRING network with this gene set and limiting active interaction sources to experiments and databases, we obtained a protein–protein interaction enrichment p value of 1.1 × 10 −16 .…”

“…Due to space limitations, we summarize additional genes implicated in EOAD risk in Table 1 . These include SORL1 [ 202 , 211 – 215 ], reviewed in [ 173 ]; ABCA7 [ 216 – 218 ], reviewed in [ 219 ]; TREM2 [ 220 , 221 ]; TYROBP [ 222 , 223 ]; PSD2 [ 3 ]; NOTCH3 [ 224 ]; HTRA1 [ 225 ]; CHCHD10 [ 225 ], reviewed in [ 208 ]; PARK2 [ 194 ]; and several others. To explore the relationships between these genes, we performed a network analysis using the STRING database, which highlighted an intriguing, putative mechanistic connection between HTRA1 and EOAD risk (Fig.…”

Codon Usage is Influenced by Compositional Constraints in Genes Associated with Dementia

“…ApoE, CLU, CR1, CD33, ABCA7, and MS4A are considered genes responsible for the late onset of AD genes ( Bates et al, 2009 ). A large study conducted in South China encompassing 1795 patients with neurodegenerative dementias and pathogenic variants of PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, and SIGMAR1 genes and abnormal repeat expansions in C9orf72 and HTT was observed, and among all, PSEN1 gene was mutated frequently ( Jiao et al, 2021 ). The mutated genes result in the production of abnormal proteins.…”