Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated proteogenomic analysis for inherited bone marrow failure syndrome (IBMFS) was performed to reveal their biological features and to develop a proteomic-based diagnostic assay in the discovery cohort; dyskeratosis congenita (n = 12), Fanconi anemia (n = 11), Diamond–Blackfan anemia (DBA, n = 9), Shwachman–Diamond syndrome (SDS, n = 6), ADH5/ALDH2 deficiency (n = 4), and other IBMFS (n = 18). Unsupervised proteomic clustering identified eight independent clusters (C1–C8), with the ribosomal pathway specifically downregulated in C1 and C2, enriched for DBA and SDS, respectively. Six patients with SDS had significantly decreased SBDS protein expression, with two of these not diagnosed by DNA sequencing alone. Four patients with ADH5/ALDH2 deficiency showed significantly reduced ADH5 protein expression. To perform a large-scale rapid IBMFS screening, targeted proteomic analysis was performed on 417 samples from patients with IBMFS-related hematological disorders (n = 390) and healthy controls (n = 27). SBDS and ADH5 protein expressions were significantly reduced in SDS and ADH5/ALDH2 deficiency, respectively. The clinical application of this first integrated proteogenomic analysis would be useful for the diagnosis and screening of IBMFS, where appropriate clinical screening tests are lacking.

深度独立于数据的蛋白质组学分析的最新进展已经能够对超过 10,000 种蛋白质进行全面的定量分析。在此，对遗传性骨髓衰竭综合征（IBMFS）进行了综合蛋白质组学分析，以揭示其生物学特征，并在发现队列中开发基于蛋白质组学的诊断测定法；先天性角化不良 ( n  = 12)、Fanconi 贫血 ( n  = 11)、Diamond-Blackfan 贫血 (DBA，n  = 9)、Shwachman-Diamond 综合征 (SDS，n  = 6)、ADH5/ALDH2 缺乏症 ( n  = 4)、和其他 IBMFS（n  = 18）。无监督的蛋白质组聚类鉴定出八个独立的簇（C1-C8），其中核糖体途径在 C1 和 C2 中特异性下调，分别富集 DBA 和 SDS。六名 SDS 患者的 SBDS 蛋白表达显着降低，其中两名患者仅通过 DNA 测序无法诊断。四名 ADH5/ALDH2 缺陷患者的 ADH5 蛋白表达显着降低。为了进行大规模的快速 IBMFS 筛查，对来自 IBMFS 相关血液疾病患者 ( n  = 390) 和健康对照 ( n  = 27) 的 417 份样本进行了靶向蛋白质组分析。 SDS 和 ADH5/ALDH2 缺陷时 SBDS 和 ADH5 蛋白表达分别显着降低。在缺乏适当的临床筛查测试的情况下，首次集成蛋白质基因组分析的临床应用将有助于 IBMFS 的诊断和筛查。