Bi-allelic variants inWNT7Bdisrupt the development of multiple organs in humans

Abstract

BackgroundPulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants inRARBandSTRA6, which have been previously associated with this disorder.MethodsWe sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants.ResultsWe identified bi-allelic variants inWNT7Bin fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found thatwnt7bbmutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures.ConclusionOur findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT–β-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.

A founder variant expands the phenotype of WNT7B‐related PDAC syndrome

“…17,20,21 It is worth mentioning that we have previously shown that this role seems to be conserved in zebrafish where wnt7bb mutants display abnormal development of the swimbladder, the lung equivalent in zebrafish. 4 Abnormal tracheal development is another PDAC phenotype that is recapitulated in mice with WNT7B deficiency, which display incomplete cartilaginous rings. 21 Macrophage-induced apoptosis mediated by Wnt7b has been proposed as the mechanism for why Wnt7b deficient mice display pulmonary vascular defects and persistence of the hyaloid artery in the developing eye.…”

“…Besides the compelling human genetics data, WNT7B was an attractive candidate biologically. Indeed, we have shown that wnt7bb mutant zebrafish recapitulated a key phenotypic aspect of PDAC syndrome, that is, malformed swimbladder, the equivalent of lung hypoplasia in humans 4 . However, this association is not yet listed in OMIM pending independent confirmation and the current classification of the link between WNT7B and PDAC syndrome remains “Moderate” according to the ClinGen guidelines 5 .…”

“…Recently, we reported three families in which biallelic missense and nonsense variants in WNT7B were associated with a PDAC spectrum. 4 Besides the compelling human genetics data, WNT7B was an attractive candidate biologically. Indeed, we have shown that wnt7bb mutant zebrafish recapitulated a key phenotypic aspect of PDAC syndrome, that is, malformed swimbladder, the equivalent of lung hypoplasia in humans.…”

“…Indeed, we have shown that wnt7bb mutant zebrafish recapitulated a key phenotypic aspect of PDAC syndrome, that is, malformed swimbladder, the equivalent of lung hypoplasia in humans. 4 However, this association is not yet listed in OMIM pending independent confirmation and the current classification of the link between WNT7B and PDAC syndrome remains "Moderate" according to the ClinGen guidelines. 5 Here, we describe two new families that share a founder missense variant in WNT7B with a deleterious impact on WNT7B signaling.…”

“…Recently, we reported three families in which biallelic missense and nonsense variants in WNT7B were associated with a PDAC spectrum 4 . Besides the compelling human genetics data, WNT7B was an attractive candidate biologically.…”