Guan Yuhong, Zhang Xiaoyan, Tang Xiaolei, Yang Haiming, Zhao Shunying
Department II of Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Orphanet J Rare Dis. 2025 Mar 10;20(1):111. doi: 10.1186/s13023-025-03616-4.
Post-infectious bronchiolitis/bronchitis obliterans (PIBO) is a chronic irreversible obstructive lung disease that results in obstruction and/or obliteration of small airways. Previous reports have indicated that PCD-related gene mutations contribute to PIBO incidence. However, the relationship between DNAH9 variants and PIBO remains unclear. This study aimed to evaluate the association between DNAH9 mutations and the incidence of PIBO. In our cohort, 126 PIBO patients conducted Whole Exome Sequence (WES) test and twelve variants of DNAH9 gene were identified. Detailed clinical information, high-resolution computerized tomography and/or electronic bronchoscopy findings of the six pediatric children carried DNAH9 variants were systematically collected, meticulously reviewed, and rigorously analyzed. Clinical evaluation revealed three patients with bronchiolitis obliterans, two patients with bronchitis obliterans and one with both conditions. All patients had at least one previous bout of pneumonia, which in three cases was linked to Mycoplasma pneumoniae, in two cases to adenovirus infection, and in one case to co-infection with both pathogens. Genetic analysis of all cases identified six compound heterozygous DNAH9 mutations encompassing twelve variants: c.12,925 C > T (p.Arg4309*), c.5152-10G > T (-), c.4604 A > G (p.Gln1535Arg), c.12844-14T > C (-), c.4816T > C (p.Phe1606Leu), c.8831G > A (p.Arg2944Gln), c.9479 C > T (p.Ala3160Val), c.7415G > A (p.Arg2472Gln), c.5692G > T (p.Glu1898*), c.11,572 C > T (p.Arg3858Trp), c.11,176 C > T (p.Arg3726Trp), c.1010 C > T (p.Pro337Leu). These variants included two nonsense mutations, two mutations near splice sites, and eight missense mutations. All variants exhibited negligible or low minor allele frequencies based on the gnomAD database and were predicted to be variants of uncertain significance (VUS) or deleterious based on comprehensive bioinformatics analysis. Our findings suggest that DNAH9 compound complex variants may contribute to development of PIBO following severe M. pneumoniae and/or adenoviral infectious pneumonia in pediatric patients.
感染后闭塞性细支气管炎/支气管炎（PIBO）是一种慢性不可逆性阻塞性肺病，可导致小气道阻塞和/或闭塞。既往报道表明，与原发性纤毛运动障碍（PCD）相关的基因突变会导致PIBO的发生。然而，DNAH9基因变异与PIBO之间的关系仍不清楚。本研究旨在评估DNAH9突变与PIBO发病率之间的关联。在我们的队列中，126例PIBO患者进行了全外显子测序（WES）检测，共鉴定出12种DNAH9基因变异。系统收集、仔细回顾并严格分析了6例携带DNAH9变异的儿童患者的详细临床信息、高分辨率计算机断层扫描和/或电子支气管镜检查结果。临床评估显示，3例为闭塞性细支气管炎，2例为闭塞性支气管炎，1例两者兼具。所有患者既往至少有一次肺炎发作，其中3例与肺炎支原体有关，2例与腺病毒感染有关，1例与两种病原体合并感染有关。对所有病例的基因分析鉴定出6种复合杂合DNAH9突变，包含12种变异：c.12,925 C＞T（p.Arg4309*）、c.5152-10G＞T（-）、c.4604 A＞G（p.Gln1535Arg）、c.12844-14T＞C（-）、c.4816T＞C（p.Phe1606Leu）、c.8831G＞A（p.Arg2944Gln）、c.9479 C＞T（p.Ala3160Val）、c.7415G＞A（p.Arg2472Gln）、c.5692G＞T（p.Glu1898*）、c.11,572 C＞T（p.Arg3858Trp）、c.11,176 C＞T（p.Arg3726Trp）、c.1010 C＞T（p.Pro337Leu）。这些变异包括2种无义突变、2种剪接位点附近的突变和8种错义突变。基于gnomAD数据库，所有变异的次要等位基因频率均极低或可忽略不计，基于全面的生物信息学分析，这些变异被预测为意义未明的变异（VUS）或有害变异。我们的研究结果表明，DNAH9复合复杂变异可能在儿童患者严重的肺炎支原体和/或腺病毒感染性肺炎后促使PIBO的发生。
