Rare lung diseases in children: phenotyping, genetics, course and disease burden

儿童间质性肺病(CHILD)包括许多罕见的慢性疾病，通常由强烈的遗传因素引起，其发病过程在很大程度上尚不清楚。生物库儿童肺病登记处(CHILD-EU)是收集、同行审查和监测这些疾病的开放平台。在之前的资助期间，我们实施并成功应用了基于数据、分子遗传学、儿童功能和临床特征的路径，也产生了新的、可测试的假说。现在将通过应用适当的、技术先进的分子方法，在具有所需生物材料的仔细分型的患者群体中回答这些问题。第一个工作包将调查是否可以通过有针对性地使用先进的基因组和转录组分析来提高儿童病因解决病例的比例至少10%。第二个工作包将使用一大批持续性婴儿呼吸过速(NEHI)家庭来调查病因相关基因是否位于我们在1号染色体上确定的候选区域的假说。在第三个工作包中，我们将调查儿童肺纤维化是否对长期结局产生不利影响，继发性肺动脉高压是否没有影响，以及有儿童和肺外器官表现的婴儿是否发病率增加和生活质量下降。我们期望从分子上阐明新的疾病实体，提高他们的基因诊断，并阐明儿童肺纤维化、肺高压、合并症对儿童间质性肺病患者远期病程的影响。

Childhood interstitial lung diseases (chILD) comprises many, rare chronic diseases, often caused by strong genetic factors, whose disease course is largely unexplored. The Children's Lung Registry with Biobank (chILD-EU) is an open platform for the collection, peer-review, and monitoring of these diseases. In the previous funding period, we implemented and successfully applied pathways for data-based, molecular genetics, functional and clinical characterization of chILD, and also generated new, testable hypotheses. These will now be answered in carefully phenotyped patient populations with the required biomaterials, by applying appropriate, technically advanced molecular methods. The 1st work package will investigate whether the proportion of etiologically resolved cases of chILD can be increased by at least 10% by targeted use of advanced genomic and transcriptome analyses. The 2nd work package will use a large cohort of families with persistent tachypnea of infancy (NEHI) to investigate the hypothesis of whether etiologically relevant genes are located in the candidate regions we have identified on chromosome 1. In the 3rd work package, we will investigate whether pulmonary fibrosis in children adversely affects long-term outcome, whether secondary pulmonary hypertension has no effect, and whether infants with chILD and extrapulmonary organ manifestations have increased morbidity and poorer quality of life.We expect to molecularly elucidate new disease entities, improve their genetic diagnosis, and clarify the impact of childhood pulmonary fibrosis, pulmonary hypertension, and the influence of co-morbidities on the long-term course of patients with childhood interstitial lung diseases.