Biallelic DAW1 variants reveal a tissue-specific role in heterotaxy without primary ciliary dyskinesia.

DAW1

Biallelic variants of DAW1, a dynein arm assembly factor: the splice-site variant causes complete loss of function, and the missense variant p.Arg114Gln a context-dependent hypomorphic allele

Defects of motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD) and primary ciliary dyskinesia (PCD), which often co-occur although the genetic and mechanistic bases of their tissue-specific manifestations remain poorly understood. The authors identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with an HTX/laterality defect spectrum, presenting with complex CHD without extracardiac organ malposition and no evidence of PCD: whole-genome sequencing revealed a maternally inherited canonical splice-site variant (c.648+1G>A) and a paternally inherited missense variant (c.341G>A; p.Arg114Gln), both classified as variants of uncertain significance under ACMG/AMP guidelines. In Xenopus tropicalis, depletion of the DAW1 ortholog disrupts left-right patterning, cardiac looping and mucociliary flow, phenotypes rescued by expression of wild-type human DAW1; the splice-site variant results in complete loss of function in both contexts, whereas p.Arg114Gln rescues mucociliary flow but does not restore left-right patterning. These findings, which closely match the proband's phenotype, provide in the authors' view strong functional evidence to reclassify c.648+1G>A as likely pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The Xenopus rescue set-up separates what the clinic cannot: an allele that restores mucociliary flow but not laterality accounts for a heterotaxy without ciliary dyskinesia, which invites keeping a ciliary gene in mind in the face of complex heart disease without signs of PCD. For interpretation, the contribution is a functional argument usable to reclassify the splice-site variant, not a validated criterion for all variants of the gene. Everything rests, however, on a single proband: without a second family, the relationship between DAW1 and human heterotaxy remains to be confirmed, and the status of a context-dependent hypomorphic allele has been established only in the amphibian model.

Analysis by Dr Thibaut Benquey