ODAD4-Related Primary Ciliary Dyskinesia: Report of Five Cases and a Founder Variant in Quebec.

Abstract

Pathogenic variants in ODAD4 are an ultra-rare cause of primary ciliary dyskinesia (PCD). Previously reported cases display classic disease phenotypes, including chronic oto-sino-pulmonary disease and development of bronchiectasis by adulthood. We report five individuals with PCD harboring biallelic ODAD4 variants (median age 14, range 3-41 years). Participants underwent standardized PCD diagnostic evaluations. Three individuals shared the novel homozygous ODAD4 genotype [NM_031421.5: c.245delA, p.(Lys82Argfs*29)], and genealogy analysis highly suggests a founder effect in French-Canadians from two regions of Quebec. All five participants had normal pulmonary function values. Two Quebec participants lacked radiographic pneumonias or bronchiectasis (ages 14 and 38 years) despite life-long suppurative respiratory symptoms, low nasal nitric oxide levels, and outer dynein arm defects on electron microscopy. Reverse transcription polymerase chain reaction of the c.245delA variant showed abnormal splicing with in-frame skipping of exon 2, allowing expression of a mildly shortened mRNA product. However, functional analysis showed overall static cilia, absence of ODAD4 protein on Western blot, and absence of in vivo mucociliary clearance. The reason for a milder pulmonary phenotype with the c.245delA variant in ODAD4 remains unclear, but regional screening for this variant in Quebec may identify more cases and enhance understanding of this mild form of PCD.