School of Clinical Sciences, University of Bristol, Bristol, UK.
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK ; Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge, UK.
Genome Med. 2015 Apr 9;7(1):36. doi: 10.1186/s13073-015-0151-5. eCollection 2015.
Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases.
We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes.
We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician.
These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity.
遗传性出血和血小板疾病（BPD）具有异质性，且常具有未知的遗传基础。BRIDGE-BPD 研究旨在通过基于改进和标准化的深度、多系统表型分析的聚类分析，利用高通量测序发现 BPD 的新致病基因。
我们报告了一种新方法，即将 BPD 病例的临床和实验室特征用适应的人类表型本体论（HPO）术语进行注释。然后，聚类分析用于描述具有相似 HPO 术语和相同基因中变异的病例组。
我们发现，在 10 个欧洲或美国中心登记的遗传性 BPD 索引病例中，有 60%的病例被注释为 HPO 术语，表明血液或造血组织以外的器官系统存在异常，特别是神经系统。家系内的病例根据其 HPO 编码表型紧密聚集在一起，具有几种临床怀疑的综合征的病例也是如此。随后发现携带 ACTN1 变异的病例也紧密聚集在一起，即使使用登记临床医生可用的临床和实验室数据，也无法对这种最近描述的疾病进行诊断。
这些发现验证了我们针对已知 BPD 的新型基于 HPO 的表型聚类方法，从而为具有未知遗传基础的 BPD 提供了新的发现工具。这种方法也将与其他具有显著遗传异质性的罕见疾病相关。
