Late Breaking Abstract - Mutations of BRWD1 may be associated with Primary Ciliary Dyskinesia

Purpose: Patients with Primary Ciliary Dyskinesia (PCD) have been rarely reported in China, and few studies are currently available to characterize the genetic basis of PCD in Chinese families. To identify the potential causative gene in a patient with PCD, who is from a consanguineous Chinese family. Methods: Runs of homozygosity and whole-exome sequencing were conducted on the family. Sanger sequencing was conducted to validate the candidate mutations and familial segregation. Real-time QPCR was used to measure the expression level of the possible causative gene. Zebrafish experiments were performed for candidate gene function verification. Results: A homozygous change in BRWD1, an important developmental gene, that resulted in a missense mutation in the WD-repeat domain of the protein and cosegregated with PCD phenotypes in the family. This mutation in BRWD1 was predicted to be highly deleterious, and qPCR analysis showed a significant and extreme decrease in the expression level of the mutant gene in the affected individual. Morpholino knockdown of brwd1 in zebrafish embryos resulted in situs inversus totalis (a typical phenotype of PCD) and abnormal cardiac looping. Conclusions: BRWD1 was therefore implicated as a novel causative gene for Primary Ciliary Dyskinesia. This homozygous variant was not reported before.