Table_4_Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching.xlsx

IntroductionAccurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs.MethodsWe collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient.ResultsOur results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2.DiscussionThis study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs.

精确且标准化的表型描述对于罕见病的诊断及新疾病的发现至关重要。为此，人类表型本体（Human Phenotype Ontology，HPO）系统得以构建，旨在提供丰富的层级化表型描述集合。尽管针对免疫遗传缺陷的HPO术语已得到优化与维护，然而，尚未探讨这种维护是否能够提升系统性自身炎症疾病（Systemic Autoinflammatory Disease，SAID）患者的诊断准确性。本研究旨在探讨优化后的HPO术语对于SAID识别的提升作用，并展示利用维护后的HPO术语进行表型驱动基因组诊断的潜力。方法上，我们收集了来自八个不同欧洲SAID专业中心的98例基因确诊SAID患者的HPO术语，并运用LIRICAL（临床异常似然比解释）计算算法评估HPO维护对正确SAID优先级的影响。结果显示，正确诊断的比例从66%提升至86%，且最高优先级诊断的数量从38例增加至45例。在进一步的试点研究中，维护后的HPO术语亦改善了基于全外显子测序（Whole-Exome Sequencing，WES）的分析，使得在维护前有10/12的患者得到诊断，而在维护后有12/12的患者得到诊断。此外，需要解释的候选疾病数量平均从35例减少至2例。讨论部分指出，HPO术语的维护能够提升正确诊断的识别率，凸显了基于HPO的基因组诊断在SAID中的巨大潜力。