Genetic landscape of early-onset dementia in Hungary

Abstract

Introduction Early-onset dementias (EOD) are predominantly genetically determined, but the underlying disease-causing alterations are often unknown. The most frequent forms of EODs are early-onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD). Patients This study included 120 Hungarian patients with EOD (48 familial and 72 sporadic) which had a diagnosis of EOAD (n = 49), FTD (n = 49), or atypical dementia (n = 22). Results Monogenic dementia was detected in 15.8% of the patients. A pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was present in 6.7% of cases and disease-causing variants were detected in other known AD or FTD genes in 6.7% of cases (APP, PSEN1, PSEN2, GRN). A compound heterozygous alteration of the TREM2 gene was identified in one patient and heterozygous damaging variants in the CSF1R and PRNP genes were detected in two other cases. In two patients, the coexistence of several heterozygous damaging rare variants associated with neurodegeneration was detected (1.7%). The APOE genotype had a high odds ratio for both the APOE ɛ4/3 and the ɛ4/4 genotype (OR = 2.7 (95%CI = 1.3–5.9) and OR = 6.5 (95%CI = 1.4–29.2), respectively). In TREM2, SORL1, and ABCA7 genes, 5 different rare damaging variants were detected as genetic risk factors. These alterations were not present in the control group. Conclusion Based on our observations, a comprehensive, targeted panel of next-generation sequencing (NGS) testing investigating several neurodegeneration-associated genes may accelerate the path to achieve the proper genetic diagnosis since phenotypes are present on a spectrum. This can also reveal hidden correlations and overlaps in neurodegenerative diseases that would remain concealed in separated genetic testing.

A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes

“…The SORL1 (sortilin-related receptor 1) gene encodes a transmembrane protein, named sortilin-related receptor (SORLA), involved in endo-lysosomal processes, amyloid precursor protein (APP) sorting and in the degradation of amyloid-beta (Ab) peptide, responsible for Alzheimer’s disease (AD) pathology [ 68 , 69 ]. Initially, both common and rare SORL1 variants have been associated with AD [ 70 , 71 , 72 ], while recently, deleterious variants have been also detected in frontotemporal lobar degeneration (behavioral variant and primary progressive aphasia), and dementia with Lewy bodies (DLB) [ 28 , 63 , 73 , 74 , 75 ]. For this reason, SORL1 is considered a cross-disease gene.…”

Study protocol of the Hungarian Longitudinal Study of Healthy Brain Aging (HuBA)

“…Part of it will be forwarded to a clinical laboratory (Semmelweis Egyészségügyi Kft., Budapest, Hungary) for apolipoprotein E genotyping, B12 and TSH measurements. Sample processing is performed as described previously 23 . The rest of the anticoagulated blood is fractioned into plasma, platelets, red blood cells, and white blood cells by centrifuging at 2000g at 4°C for 10 minutes within 30 minutes of obtaining.…”

“…Sample processing is performed as described previously 23 . The rest of the anticoagulated blood is fractioned into plasma, platelets, red blood cells, and white blood cells by centrifuging at 2000g at 4°C for 10 minutes within 30 minutes of obtaining.…”

Recent research advances in young-onset dementia

“…The APOEε4 allele is a risk factor for developing AD in older people but the impact of this allele on younger people remains inconsistent [47]. Next generational sequencing such as specific panels [48,49], whole exome sequencing [50] and whole genome sequencing [51] are being utilized internationally and may increase diagnostic yield in YOD. Sophisticated genetic analysis and machine learning has also identified shared genetic overlap [52 ▪ ], structural neuroimaging and clinical data [53 ▪▪ ] between FTD and schizophrenia, which furthers understanding between overlapping pathophysiology and clinical symptoms.…”