Heterotaxy Is Associated with Previously Unrecognised Ciliary Defects Independent of Primary Ciliary Dyskinesia

Background Heterotaxy (HTX) describes abnormal left-right arrangement of the organs, often associated with complex congenital heart disease (CHD). HTX is enriched in the respiratory condition primary ciliary dyskinesia (PCD) due to defective nodal cilia. A subset of patients presents with HTX and mild respiratory phenotypes but normal respiratory cilia function. The mechanisms underlying situs defects in these non-PCD patients remain unclear. Methods Retrospective diagnostic data were analysed from 73 HTX patients who had been referred to the Royal Brompton Hospital PCD Diagnostic Service (1997 to 2023). Data included clinical history, high-speed video microscopy, transmission electron microscopy of ciliary ultrastructure, PCD genotype and clinical imaging for cardiac and abdominal situs. Results 30 patients were diagnosed with PCD, and 43 patients did not have PCD. CHD was observed in both PCD and non-PCD groups. Atrioventricular discordance was more frequent in non-PCD HTX (20.9% vs 0%; p=0.0102). Midline Liver position was also enriched in the non-PCD HTX group compared to PCD patients with HTX (54.3% vs 25.9% p=0.0377). TEM revealed 24.4% of the non-PCD patients had extra ciliary microtubules and 24.4% demonstrated microtubular disorganization. Review of diagnostic results from 2,823 referred patients showed a higher incidence of ultrastructural ciliary anomalies, such as extra microtubules or microtubular disorganisation, in individuals with CHD who did not have PCD (p=0.04 when compared to patients without CHD, regardless of HTX). Quantitative ciliary function assessment demonstrated preserved or higher ciliary beat amplitude in non-PCD HTX compared to PCD patients. Conclusions In conclusion, HTX can be linked to respiratory ciliary dysfunction, even in patients without classical PCD. Subtle ciliary defects in non-PCD HTX patients associate with higher rates of CHD and abnormal organ situs. Genetic and phenotypic diversity in HTX highlights the need for expanded genetic testing and future multicentre studies to assess outcome.