Respiratory ciliary abnormalities in heterotaxy beyond primary ciliary dyskinesia: functional and ultrastructural characterisation

Background Heterotaxy (HTX) is characterised by abnormal left-right arrangement of the internal organs and is frequently associated with complex congenital heart disease (CHD). HTX is enriched among patients with primary ciliary dyskinesia (PCD), due to impaired function of embryonic nodal cilia involved in left-right patterning. However, a subset of patients with HTX presents with mild or absent respiratory phenotypes and normal respiratory ciliary function, and the mechanisms underlying situs abnormalities in these non-PCD patients remain unclear. We aimed to compare the clinical history, respiratory ciliary structure, and ciliary function of patients with HTX with and without PCD. Methods Retrospective diagnostic data were analysed from 73 subjects with HTX referred to the Royal Brompton Hospital PCD Diagnostic Service between 1997 and 2024. Of these, 30 were diagnosed with PCD (HTX-PCD) and 43 did not meet the diagnostic criteria for PCD (HTX-only). Data included clinical history, high-speed video-microscopy (HSVM), transmission electron microscopy (TEM) of ciliary ultrastructure, PCD genotype and cardiac and thoracic/abdominal situs imaging. Results Atrioventricular discordance (p = 0.0102) and midline liver position (p = 0.0377) were more frequent in the HTX-only group. TEM analysis identified extra microtubules in 24.4% of HTX-only subjects and microtubular disorganisation in 24.4%. Review of TEM data from 2,823 individuals referred for PCD assessment demonstrated that these ultrastructural abnormalities were associated with an increased prevalence of CHD (p = 0.04). Quantitative HSVM analysis demonstrated preserved or increased ciliary beat amplitude in HTX-only compared with HTX-PCD patients. Discussion HTX without PCD is associated with distinct laterality phenotypes and subtle respiratory ciliary abnormalities below current PCD diagnostic thresholds. These findings suggest that mild defects affecting ciliary structure and function may contribute to abnormal left-right patterning without causing classical PCD. Larger multicentre genetic and phenotypic studies are required to further define the mechanisms underlying HTX.