Institute of Genomic Medicine and Rare Disorders, Semmelweis University, 1082, Budapest, Hungary.
PentaCore Laboratory Budapest, Budapest, Hungary.
Neurol Sci. 2022 Sep;43(9):5289-5300. doi: 10.1007/s10072-022-06168-8. Epub 2022 Jun 25.
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).
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).
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.
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.
早发性痴呆（EOD）主要由遗传决定，但导致疾病的潜在变化通常未知。最常见的 EOD 形式是早发性阿尔茨海默病（EOAD）和额颞叶痴呆（FTD）。
本研究纳入了 120 名匈牙利 EOD 患者（48 名家族性和 72 名散发性），这些患者的诊断为 EOAD（n=49）、FTD（n=49）或非典型痴呆（n=22）。
15.8%的患者检测到单基因性痴呆。6.7%的病例中存在 C9ORF72 基因的致病性六核苷酸重复扩展，6.7%的病例中发现了其他已知的 AD 或 FTD 基因的致病变异（APP、PSEN1、PSEN2、GRN）。一名患者被鉴定出 TREM2 基因的复合杂合性改变，另两名患者被检测出 CSF1R 和 PRNP 基因的杂合性有害变异。在两名患者中，检测到几种与神经退行性变相关的杂合性有害罕见变异的共存（1.7%）。APOE 基因型对 APOE ɛ4/3 和 ɛ4/4 基因型均具有高比值比（OR=2.7（95%CI=1.3-5.9）和 OR=6.5（95%CI=1.4-29.2））。在 TREM2、SORL1 和 ABCA7 基因中，作为遗传风险因素，检测到 5 种不同的罕见有害变异。这些改变在对照组中不存在。
根据我们的观察，对几个与神经退行性变相关的基因进行全面的、靶向的下一代测序（NGS）检测可以加速获得适当的遗传诊断的进程，因为表型呈谱性分布。这也可以揭示神经退行性疾病中隐藏的相关性和重叠性，而这些在单独的基因检测中可能是隐藏的。
