Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype

Area of Science:

• Medical Genetics
• Cell Biology
• Developmental Biology

Background:

• Primary ciliary dyskinesia (PCD) is a genetic disorder affecting cilia function.
• Organ laterality abnormalities, such as situs inversus and heterotaxy, are observed in some PCD patients.
• The precise relationship between specific ciliary defects and laterality disorders in PCD remains unclear.

Purpose of the Study:

• To investigate the association between distinct ciliary ultrastructural defects or genotypes and the presence or type of organ laterality abnormalities in individuals with PCD.
• To determine if specific ciliary defects predict the likelihood of laterality defects in PCD.

Main Methods:

• A multicenter, prospective study enrolled participants with PCD.
• Participants were categorized based on their identified ciliary ultrastructural defect or genetic genotype.
• Retrospective analysis using logistic regression evaluated the association between ciliary defects and laterality abnormalities, adjusting for variant types.

Main Results:

• Among 559 participants, situs solitus, situs inversus totalis, and situs ambiguus were observed in 51.2%, 38.5%, and 10.4%, respectively.
• Laterality defects were significantly more common in patients with outer dynein arm defects (OR, 2.07) compared to those with inner dynein arm defects and microtubular disorganization.
• Conversely, laterality defects were less likely in individuals with normal/near-normal ciliary ultrastructure (OR, 0.04).
• Heterotaxy occurred in 4.5% of the outer dynein arm defects group but was absent in the inner dynein arm defects with microtubular disorganization group.

Conclusions:

• The risk of developing organ laterality abnormalities in primary ciliary dyskinesia varies depending on the specific underlying ciliary ultrastructural defect.
• Outer dynein arm defects are associated with an increased likelihood of laterality defects, including heterotaxy.
• Further research is needed to elucidate the pathophysiological mechanisms driving these observed differences in laterality defects within PCD.