Genetic Disorder of Mucocilary Clearance

描述(申请人提供)：这个由10个地理分散的临床研究站点组成的联合体将继续研究与粘膜纤毛清除缺陷和呼吸道宿主防御机制缺陷相关的罕见的呼吸道疾病，这些疾病会导致慢性呼吸道感染和/或支气管扩张。这些疾病包括原发性睫状肌运动障碍(PCD)、特发性支气管扩张症(IB)、囊性纤维化(CF)、非结核分枝杆菌(NTM)呼吸道感染、罕见的免疫疾病(例如RAG1缺陷)以及由DNAH5(Chr5p)突变引起的合并PCD的Cri du Chat综合征(chr 5pminus；缺失)。在该联盟过去5年的工作中，我们取得了显著的进展，已经对临床实践产生了影响，特别是在PCD和相关疾病方面。一项重大进展是开发了一种无创检测PCD(鼻腔一氧化氮，NO)的方法。这项测试现在已被确认为PCD的一种有用的临床测试，我们正在参与欧洲BESTCILIA赠款，以帮助他们在欧洲实施我们的NNO测试方法。我们的联盟在确定28个基因中导致PCD的突变方面发挥了关键作用，我们认为这将导致PCD患者中PCD的遗传原因。我们已经开发了一个包含这28个基因(AmpliSeq)的基因测试小组，该小组正在进行技术验证。在临床方面，我们发现导致PCD的突变与异位和先天性心脏病(CHD)有关。这一发现导致了后续研究，这些研究显示，先天性心脏病异位症患者术后的临床结果更差，并导致了对冠心病患者进行遗传学研究的呼吁。沿着不同的思路，我们开发了一种针对PCD的严格的生活质量(QOL)量表，这将是PCD治疗临床试验的关键结果衡量标准。最后，我们开发了新的初步数据，即特发性支气管扩张患者与遗传性结缔组织疾病(包括硬膜扩张)具有相同的表型特征，这可能反映了潜在的遗传变异。总之，拟议的工作将导致罕见呼吸道疾病的更早诊断、更好的护理和更有效的治疗干预。

DESCRIPTION (provided by applicant): This Consortium of 10 geographically-dispersed clinical research sites will continue to study rare diseases of the airways that are associated wit defective mucociliary clearance and airway host defense mechanisms, which result in chronic airways infection and/or bronchiectasis. These disorders include Primary Ciliary Dyskinesia (PCD), idiopathic bronchiectasis (IB), cystic fibrosis (CF), airway infection with non-tuberculous mycobacteria (NTM), rare immune disorders (e.g., RAG1 deficiency), and Cri du Chat syndrome (chr 5pminus; deletion) complicated by concomitant PCD, caused by mutations in DNAH5 (chr5p). Over the past 5 years of this Consortium's work, we have made remarkable progress that is already impacting on clinical practice, particularly in PCD and associated disorders. One major advance was the development of a non-invasive test for PCD (measurement of nasal nitric oxide, NO). This test is now validated as a useful clinical test for PCD, and we are participating in the European BESTCILIA grant to help them implement our methodology for nNO testing in Europe. Our Consortium played a critical role in identifying PCD-causing mutations in 28 genes, which we think will be responsible for the genetic cause of PCD in > 70%) of PCD patients. We have developed a genetic test panel containing those 28 genes (Ampliseq), which is being technically validated. On the clinical side, we discovered that PCD-causing mutations are associated with heterotaxy and congenital heart disease (CHD). This discovery resulted in follow-up studies, which showed worse post-operative clinical outcomes for CHD-heterotaxy patients, and has led to a call for genetic studies of patients with CHD. Along different lines, we developed a rigorous quality-of-life (QOL) instrument for PCD, which will be a key outcome measure for therapeutic clinical trials in PCD. Finally, we have developed novel preliminary data that patients with idiopathic bronchiectasis share phenotypic features with heritable connective tissue disorders, including dural ectasia, which may reflect underlying genetic variants. Taken together, the proposed work will lead to earlier diagnoses, improved care, and more effective therapeutic interventions for rare airway diseases.