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Published on: May 30, 2020
DNAH9 variants in children with post-infectious bronchiolitis/bronchitis obliterans
Yuhong Guan1, Xiaoyan Zhang1, Xiaolei Tang1
1Department 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.
Insights
Genetic variants in the DNAH9 gene may contribute to post-infectious bronchiolitis/bronchitis obliterans (PIBO) in children following severe pneumonia. This study identified complex DNAH9 mutations in PIBO patients, suggesting a potential genetic link to this irreversible obstructive lung disease.
Area of Science:
- Genetics
- Pulmonology
- Pediatrics
Background:
- Post-infectious bronchiolitis/bronchitis obliterans (PIBO) is a chronic obstructive lung disease affecting small airways.
- Previous research suggests a link between PCD-related gene mutations and PIBO.
- The specific role of DNAH9 variants in PIBO pathogenesis is not well understood.
Purpose of the Study:
- To investigate the association between DNAH9 gene mutations and the incidence of PIBO in a pediatric cohort.
- To identify and characterize DNAH9 variants in patients diagnosed with PIBO.
- To explore the clinical and genetic factors contributing to PIBO development.
Main Methods:
- Whole Exome Sequencing (WES) was performed on 126 PIBO patients to identify DNAH9 variants.
- Detailed clinical information, high-resolution CT, and/or electronic bronchoscopy data were collected for pediatric patients with DNAH9 variants.
- Bioinformatic analysis was used to predict the pathogenicity of identified DNAH9 variants.
Main Results:
- Twelve variants in the DNAH9 gene were identified across six pediatric PIBO patients, including compound heterozygous mutations.
- The identified variants comprised two nonsense, two splice site, and eight missense mutations.
- All variants had low allele frequencies and were predicted as variants of uncertain significance or deleterious.
Conclusions:
- Compound complex variants in the DNAH9 gene may play a role in the development of PIBO.
- PIBO in these pediatric patients followed severe Mycoplasma pneumoniae and/or adenoviral pneumonia.
- Further research is warranted to elucidate the precise mechanisms linking DNAH9 variants to PIBO.
Abstract:
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.
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