Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype
Andrew T. Barber, Adam J. Shapiro, Stephanie D. Davis, Thomas W. Ferkol, Jeffrey J. Atkinson, Scott D. Sagel, Sharon Dell, Kenneth N. Olivier, Carlos Milla, Margaret Rosenfeld, Lang Li, Feng‐Chang Lin, Kelli M. Sullivan, Nicole A. Capps, Maimoona A. Zariwala, Michael R. Knowles, Margaret W. Leigh
Abstract
Abstract Rationale The association between organ laterality abnormalities and ciliary ultrastructural defect or genotype in primary ciliary dyskinesia is poorly understood. Objectives To determine if there is an association between presence and/or type of laterality abnormality and ciliary ultrastructural defect or genotype. Methods Participants with primary ciliary dyskinesia in a multicenter, prospective study were grouped based on ciliary ultrastructural defect or genotype. In a retrospective analysis of these data, the association of ciliary ultrastructural defect or genotype and likelihood of a laterality abnormality was evaluated by logistic regression adjusted for presence of two loss-of-function versus one or more not–loss-of-function variants. Results Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%). Compared with the group with inner dynein arm defects with microtubular disorganization, laterality defects were more likely in the outer dynein arm defects group (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.21–3.54; P < 0.01) and less likely in the normal/near normal ultrastructure group (OR, 0.04; 95% CI, 0.013–0.151; P < 0.01). Heterotaxy was present in 11 of 242 (4.5%) in the outer dynein arm defects group but 0 of 96 in the inner dynein arm defects with microtubular disorganization group (P = 0.038). Conclusions In primary ciliary dyskinesia, risk of a laterality abnormality differs by ciliary ultrastructural defect. Pathophysiologic mechanisms underlying these differences require further exploration.