Genotype–Laterality Associations in DNAAF11-Related Primary Ciliary Dyskinesia: Functional Characterization of the p.Ile100Thr Variant

Abstract Background Defects in motile ciliary function can affect respiratory health and embryonic left–right patterning. DNAAF11 , formerly known as LRRC6 , encodes a protein required for normal axonemal dynein arm assembly. The effects of individual rare missense variants and their relationships with laterality phenotypes remain incompletely characterized. We investigated the DNAAF11 c.299T > C (p.Ile100Thr) variant and reviewed the laterality spectrum of DNAAF11 -associated PCD. Methods A patient with chronic respiratory disease and situs inversus totalis underwent whole-exome sequencing and Sanger validation. Structural modeling was used to explore the potential effects of p.Ile100Thr. Wild-type and variant DNAAF11 constructs were expressed in HEK293T cells, and mRNA and protein abundance were assessed by quantitative PCR and Western blotting, respectively. Published DNAAF11 genotypes and laterality phenotypes were reviewed. Results A homozygous DNAAF11 c.299T > C (p.Ile100Thr) variant was identified in an adult woman with bronchiectasis, chronic productive cough, and situs inversus totalis; both parents were heterozygous carriers. Structural modeling suggested possible local changes around residue 100. Compared with the wild-type construct, the variant construct showed a modest reduction in mRNA abundance and a more pronounced reduction in protein abundance. The literature-based analysis included 63 patients, including the present case. Laterality information was available for 51 patients, of whom 29 had laterality abnormalities. Several recurrent variants occurred in individuals with different laterality phenotypes. After transcript harmonization, p.Ile100Thr was identified in three patients: the present homozygous case and two previously reported compound-heterozygous cases. Conclusions Reduced protein abundance provides additional experimental evidence relevant to the interpretation of DNAAF11 p.Ile100Thr. The reviewed cases demonstrate variable laterality phenotypes among individuals carrying recurrent DNAAF11 variants, but do not establish variant-specific associations with organ situs. Further studies in motile-ciliated cells are needed to determine the effects of p.Ile100Thr on dynein arm assembly and ciliary function.