Investigating genotype-phenotype correlations in primary ciliary dyskinesia: a sibling cohort study

Primary Ciliary Dyskinesia (PCD) is a complex mostly autosomal recessive disorder characterized by dysfunction of primary motor cilia, leading to multisystemic manifestations, primarily affecting the rhino-sinopulmonary system. Despite advancements in understanding its pathogenesis, genotype-phenotype correlations are not fully elucidated. Utilizing sibling cohorts offers a promising approach to investigate these genotype-phenotype correlations in PCD.

This retrospective cohort study, conducted from 2010 to 2023 at Soroka University Medical Center in Be'er-Sheva, Israel, included patients with a confirmed diagnosis of PCD. Variables and outcomes compared include typical presenting symptoms, lung function, structural changes in chest tomography (CT), and anthropometric data.

Seventeen sibling patients from eight families met the inclusion criteria. At the last follow-up visit, the median age was 16 years. Genetic diagnosis revealed homozygous pathogenic variants including DNAH11, DNAAF3, DNAL1, and ZMYND10. Full concordance rates were observed for unexplained neonatal respiratory distress, chronic cough, and rhinosinusitis in patients with DNAH11 mutations. The family with the DNAAF3 mutation exhibited the lowest difference in Forced Expiratory Volume in 1 s (FEV1) Z-scores (0.48), but the highest differences in Forced Vital Capacity (FVC) Z-scores (3.39). High differences in FEV1 Z-scores were identified in the family with the DNAL1 mutation (2.06), while the lowest differences in FVC Z-scores (0.39) were observed in the same family.

High concordance rates for certain mutations in clinical features suggest potential genotype-phenotype correlations, in contrast to weak concordance in lung function. Challenges remain in establishing direct correlations between genetic mutations and clinical outcomes.