Genetic risk factors for laterality defects and congenital heart disease (CHD) in patients with primary ciliary dyskinesia (PCD)

Abstract

PCD is a clinically and genetically heterogeneous condition in which motile ciliary defects give rise to respiratory disease and abnormal organ positioning (situs) in ~50% of patients. This can be complicated by CHD and visceral and vascular abnormalities. CHD has been reported in 3.5-6% of patients in studies based in the USA. Mutations in most but not all PCD genes have been associated with situs abnormalities. However, much remains unknown about clinical and genetic risk factors for situs and laterality defects (LD). Clinical and diagnostic data from 389 PCD patients were analysed to determine the prevalence of situs and LD and the underlying clinical and genetic risk factors. 51% had abnormal situs and 25% had CHD and/or LD (11% CHD, 8% LD, 6% both). Strikingly, patients with mutations in a subset of 9 PCD genes all had normal situs. Univariate modelling showed that patients with consanguineous parents (43%) had higher odds ratio (1.77) of situs abnormalities than those with non-consanguineous parents (p=0.02, 95% CI [1.09, 2.88]). CHD was observed in the normal and abnormal situs groups. However, patients with abnormal situs had higher odds (7.98) of having CHD and/or LD than those with normal situs (p The prevalence of CHD and LD identified in this cohort is higher than previously reported. Analysis of situs abnormality according to genotype reinforces the clear stratification of a subset of PCD genes not associated to situs abnormalities. Parental consanguinity is a risk factor for situs abnormalities. Situs abnormality is a risk factor for CHD and/or LD. Ciliopathy mutations may represent an unrecognised cause of CHD.