Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, National Heart and Lung Institute, London, UK.
Division of Services for Women and Children, Women's and Newborn Unit Bradford Royal Infirmary, University of Bradford, Bradford, UK.
Thorax. 2018 Feb;73(2):157-166. doi: 10.1136/thoraxjnl-2017-209999. Epub 2017 Aug 8.
Primary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal.
To determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive.
Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay.
Sixteen of 86 (19%) patients carried a homozygous p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting p.His154Pro patients without situs inversus are missed.
The p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests.
原发性纤毛运动障碍是一种遗传性异质性疾病，其特征是由于纤毛功能异常导致进行性肺部疾病。大约一半的患者有 situs inversus。据估计，英国南亚人群中原发性纤毛运动障碍的患病率为 1:2265。早期、准确的诊断是实施适当治疗的关键，但临床诊断测试可能存在不确定性。
确定对具有典型临床表型的英国南亚人群进行原发性纤毛运动障碍的基因筛查的重要性，这些人群的标准检测结果不确定。
对 86 名具有符合原发性纤毛运动障碍临床病史的南亚患者进行下一代测序。测试 p.His154Pro 错义变异与其他动力蛋白臂相关基因突变对诊断/表型变异性的影响。通过寡聚化测定评估 CCDC103 p.His154Pro 变体的致病性。
86 名患者中有 16 名（19%）携带纯合性 p.His154Pro 突变，该突变导致蛋白寡聚化破坏。获得了可变的诊断测试结果，包括正常的鼻内一氧化氮水平、正常的纤毛运动模式和频率以及部分和正常动力蛋白臂保留的谱。15 名（94%）患者或其兄弟姐妹（s）存在 situs inversus，提示没有 situs inversus 的 p.His154Pro 患者被遗漏。
p.His154Pro 突变在南亚人群中的流行率高于先前认为的，并且引起原发性纤毛运动障碍，使用基于病理学的临床测试可能难以诊断。当存在具有不确定标准诊断测试的强烈临床表型时，基因测试至关重要。
