Biallelic DAW1 variants reveal a tissue-specific role in heterotaxy without primary ciliary dyskinesia.
Dana Urbatsch, Anburaj Jeyaraj, Shruti Bedekar et al.
✦ AI-curated · Sources linked
Case in brief
A proband with a laterality-defect spectrum and complex congenital heart disease had no extracardiac organ malposition and no evidence of primary ciliary dyskinesia. Whole-genome sequencing identified compound heterozygous DAW1 variants: a maternally inherited canonical splice-site variant and a paternally inherited p.Arg114Gln missense variant, both initially classified as variants of uncertain significance. In Xenopus, Daw1 depletion disrupted left-right patterning, cardiac looping, and mucociliary flow. Patient-allele testing showed that p.Arg114Gln rescued mucociliary flow but not left-right patterning, whereas the splice-site variant had no rescue in either context, supporting variant reclassification.
What made this case unusual
The patient had complex congenital heart disease and laterality defects without extracardiac organ malposition or clinical evidence of primary ciliary dyskinesia. Functional testing also showed that the p.Arg114Gln allele behaved differently across developmental contexts, rescuing mucociliary flow but not left-right patterning.
Diagnostic / clinical pearl
Absence of primary ciliary dyskinesia does not exclude a DAW1-related laterality disorder. Functional assessment across relevant tissues or developmental processes may clarify the significance of DAW1 variants when clinical manifestations are tissue-specific.
Why it matters
The Xenopus assays provided functional evidence supporting reclassification of the splice-site variant as likely pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele.