{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T10:30:24Z","timestamp":1769769024078,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,29]]},"group-title":"Genetic and Genomic Medicine","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,29]]},"abstract":"<jats:p>Defects in motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD), and primary ciliary dyskinesia (PCD). Although these conditions often co-occur, the genetic and mechanistic bases for tissue-specific manifestations remain poorly understood. Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with HTX and complex congenital heart disease but no clinical signs of PCD. Whole-genome sequencing revealed a maternally inherited canonical splice-site variant (c.648+1G&gt;A) and a paternally inherited missense variant (c.341G&gt;A; p.Arg114Gln), both classified as variants of uncertain significance under ACMG\/AMP guidelines. Using Xenopus tropicalis, we show that Daw1 depletion disrupts left-right patterning, cardiac looping, and mucociliary flow, all of which are rescued by wild-type human DAW1. Functional testing of patient alleles showed notable tissue specificity: p.Arg114Gln fully rescued mucociliary flow but did not restore left-right patterning, while the splice-site variant resulted in a complete loss of function in both contexts. These findings closely match the proband's clinical phenotype and provide strong functional evidence to support reclassifying c.648+1G&gt;A as pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele. This study establishes functional criteria for interpreting DAW1 variants, shows how developmental context clarifies genotype-phenotype relationships, and highlights how in vivo models can support ACMG reclassification of unresolved HTX-related variants.<\/jats:p>","DOI":"10.64898\/2026.01.27.26344789","type":"posted-content","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T18:50:25Z","timestamp":1769712625000},"source":"Crossref","is-referenced-by-count":0,"title":["Compound heterozygous DAW1 variants reveal tissue-specific roles in left-right patterning and congenital heart disease without primary ciliary dyskinesia"],"prefix":"10.64898","author":[{"given":"Dana","family":"Urbatsch","sequence":"first","affiliation":[{"name":"Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anburaj","family":"Jeyaraj","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shruti","family":"Bedekar","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5831-1720","authenticated-orcid":false,"given":"Venkatramanan","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelby C","family":"White","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Garrod","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Peroutka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aakrosh","family":"Ratan","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Virginia, Charlottesville, VA 22903, United States;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0882-6478","authenticated-orcid":false,"given":"Saurabh S.","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, United States; Department of Biology, University of Virginia, Charlottesville, VA 22903, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.27.26344789","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T18:50:25Z","timestamp":1769712625000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.01.27.26344789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,29]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.01.27.26344789","relation":{},"subject":[],"published":{"date-parts":[[2026,1,29]]},"subtype":"preprint"}}