Genotype and pulmonary function in children with primary ciliary dyskinesia: a cross-sectional cohort study

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder with variable clinical severity. Genotype-associated differences in pulmonary function remain incompletely characterized, particularly in exclusively pediatric cohorts. This retrospective cross-sectional study included 44 children with molecularly confirmed PCD based on biallelic pathogenic or likely pathogenic variants. Clinical characteristics and spirometric parameters were compared across genotype-based groups. Exploratory gene-level comparisons were performed for the most frequently represented genotypes. Multivariable linear regression assessed associations between DNAH5, DNAH11, and CCDC39/CCDC40 and FEV1 z-score after adjustment for age at diagnosis, BMI z-score, and bronchiectasis. The median age at diagnosis was 8.7 years (IQR 6-13), and parental consanguinity was present in 59.1% of patients. DNAH5 was the most frequently identified gene (22.7%), followed by DNAH11 and CCNO (13.6% each). FEV1% predicted, FEV1 Z-score, FVC Z-score, FEF25-75, FEF25-75% predicted, and FEV1/FVC differed significantly across the genotype-based groups (all p < 0.05), with the DNAH11 group showing the most preserved pulmonary function profile. In exploratory gene-level analyses, patients with CCNO and CCDC39/CCDC40 variants demonstrated numerically lower spirometric values, whereas DNAH11 showed the most preserved values and DNAH5 an intermediate profile. In exploratory adjusted analyses, CCDC39/CCDC40 was associated with lower FEV1 z-scores (B =- 1.55, p = 0.002), whereas DNAH11 was associated with higher FEV1 z-scores (B = 1.19, p = 0.023). Neither DNAH5 nor CCNO was independently associated with FEV1 z-score.

Pulmonary function showed genotype-associated heterogeneity in this exclusively pediatric cohort with molecularly confirmed PCD. However, the gene-level findings remain exploratory because of the small subgroup sizes. Larger longitudinal multicenter studies are needed to confirm these associations.

• Primary ciliary dyskinesia is genetically and phenotypically heterogeneous, and previous large cohorts have demonstrated genotype-associated differences in pulmonary function, with poorer lung function reported particularly in CCNO and CCDC39/CCDC40 and relatively preserved function in DNAH11.

• This is one of the few exclusively pediatric cohorts to link PCD genotype with spirometric phenotype using molecularly confirmed diagnoses. • In exploratory adjusted analyses, CCDC39/CCDC40 was associated with lower FEV1 z-scores and DNAH11 with higher FEV1 z-scores, whereas DNAH5 was not independently associated with FEV1 z-score. • These findings are consistent with previously reported genotype-phenotype patterns in a pediatric population, butrequire confi rmation in larger longitudinal cohorts.