未经证实:常染色体隐性遗传戈谢病(GD)在许多国家可能未被诊断。因为芬兰确诊的GD患者数量相对较低,目前还不知道真正的患病率,据推测,芬兰可能存在未确诊的GD患者.我们先前的研究证明了Gaucher早期诊断共识评分系统的适用性(GED-CPSS;Mehta等人。,2019年)和芬兰生物库数据和样本中的大种群自动积分。确定了芬兰GD患者的指示性得分范围,但未确诊的患者未被确诊,部分原因是在评估的生物样本库人群中,高评分受试者数量较多,且缺乏适合诊断的样本.当前的研究将筛选扩展到另一个生物样本库,并评估了将自动化GED-CPSS与来自FinnGen对生物样本库供体的研究中的小核苷酸多态性(SNP)芯片基因型数据结合使用的可行性。芬兰未诊断的GD患者。此外,检测了FFPE组织和DNA恢复在GBA基因下一代测序(NGS)中的适用性。
未经评估:先前诊断为符合研究条件的芬兰GD患者,赫尔辛基生物库(HBB)中多达45,100名样本供体进行了评分。GED-C分得分,调整到本地数据,是自动化的,但也部分手动验证GD患者。目视评估稀有GBA变体的SNP芯片基因型数据。GD患者的FFPE组织从芬兰北部的HBB和BiobankBorealis(BB)获得。
UASSIGNED:纳入了3例之前诊断的GD患者和1例之前治疗过GD相关特征的患者。对接受GD相关特征治疗的患者进行了基因诊断。在本研究中,GD患者的GED-C点评分为12.5-22.5。因此,先前和当前研究的八名芬兰GD患者的得分为每名患者6-22.5分。在HBB亚群的自动得分中(N≈45,100),总分0~17.5分,其中0.77%(346/45,100)的受试者≥10分.SNP芯片基因型数据的分析能够鉴别出确诊的GD患者,但未发现GED-C评分和/或GBA基因型提示GD的潜在未确诊患者.FFPE组织DNA的恢复提高了GBANGS的质量,在六个未恢复的样本中的五个和所有四个恢复的FFPEDNA样本中证实了致病性GBA变体。
UNASSIGNED:这些发现表明,确诊患者的患病率(约1:325,000)可能确实与芬兰GD的真实患病率相对应。SNP芯片基因型数据是补充GED-CPSS筛选的有价值的工具,特别是如果基因分型管道调整为罕见的变异。这些概念验证生物库工具可以适应其他罕见的遗传疾病。
UNASSIGNED: Autosomal recessive Gaucher disease (GD) is likely underdiagnosed in many countries. Because the number of diagnosed GD patients in Finland is relatively low, and the true prevalence is currently not known, it was hypothesized that undiagnosed GD patients may exist in Finland. Our previous study demonstrated the applicability of Gaucher Earlier Diagnosis Consensus point-scoring system (GED-C PSS; Mehta et al., 2019) and Finnish biobank data and specimens in the automated point scoring of large populations. An indicative point-score range for Finnish GD patients was determined, but undiagnosed patients were not identified partly due to high number of high-score subjects in combination with a lack of suitable samples for diagnostics in the assessed biobank population. The current study extended the screening to another biobank and evaluated the feasibility of utilising the automated GED-C PSS in conjunction with small nucleotide polymorphism (SNP) chip genotype data from the FinnGen study of biobank sample donors in the identification of undiagnosed GD patients in Finland. Furthermore, the applicability of FFPE tissues and DNA restoration in the next-generation sequencing (NGS) of the GBA gene were tested.
UNASSIGNED: Previously diagnosed Finnish GD patients eligible to the study, and up to 45,100 sample donors in Helsinki Biobank (HBB) were point scored. The GED-C point scoring, adjusted to local data, was automated, but also partly manually verified for GD patients. The SNP chip genotype data for rare GBA variants was visually assessed. FFPE tissues of GD patients were obtained from HBB and Biobank Borealis of Northern Finland (BB).
UNASSIGNED: Three previously diagnosed GD patients and one patient previously treated for GD-related features were included. A genetic diagnosis was confirmed for the patient treated for GD-related features. The GED-C point score of the GD patients was 12.5-22.5 in the current study. The score in eight Finnish GD patients of the previous and the current study is thus 6-22.5 points per patient. In the automated point scoring of the HBB subpopulation (N ≈ 45,100), the overall scores ranged from 0 to 17.5, with 0.77% (346/45,100) of the subjects having ≥10 points. The analysis of SNP chip genotype data was able to identify the diagnosed GD patients, but potential undiagnosed patients with the GED-C score and/or the GBA genotype indicative of GD were not discovered. Restoration of the FFPE tissue DNA improved the quality of the GBA NGS, and pathogenic GBA variants were confirmed in five out of six unrestored and in all four restored FFPE DNA samples.
UNASSIGNED: These findings imply that the prevalence of diagnosed patients (~1:325,000) may indeed correspond the true prevalence of GD in Finland. The SNP chip genotype data is a valuable tool that complements the screening with the GED-C PSS, especially if the genotyping pipeline is tuned for rare variants. These proof-of-concept biobank tools can be adapted to other rare genetic diseases.