Identification and functional analysis of biallelic loss-of-function variants of WNT7B in a Chinese family affected with PDAC syndrome

• The first clinical case of WNT7B -related pulmonary hypoplasia, diaphragmatic anomalies, anophthalmia/microphthalmia, and cardiac defects (PDAC) syndrome in Chinese population was investigated. • Trio WES identified two novel loss-of-function variants of WNT7B . • The two novel variants decreased the RNA and protein expression of WNT7B . • The two novel variants impaired the canonical WNT-β-Catenin signaling pathway. • The study improves the strength of the gene-disease association between WNT7B and PDAC syndrome. WNT7B -related pulmonary hypoplasia, diaphragmatic anomalies, anophthalmia/microphthalmia, and cardiac defects (PDAC) syndrome is rarely reported. To date, only two each nonsense and missense variants of WNT7B were identified in five pedigrees affected with a PDAC spectrum from two independent studies. Additionally, the gene-disease association between WNT7B and PDAC syndrome is not yet clarified in OMIM database. Here, the whole exome sequencing was used to identify biallelic novel loss-of-function (LoF) variants c.324C > G (p.Tyr108*) and c.668_669dup (p.Val224Argfs*6) of WNT7B in a fetus affected with a typical PDAC spectrum, including pulmonary hypoplasia/agenesis, bilateral microphthalmia, and absence of pulmonary arteries and veins, from a Chinese family. Subsequent functional analysis revealed that the two LoF variants decreased the RNA and protein expression levels of WNT7B , and significantly impaired the canonical WNT-β-Catenin signaling pathway, which is essential for regulation of human lung development. We broaden the variant spectrum of WNT7B , and provide genetic and experimental evidence to confirm the association between WNT7B pathogenic variants and PDAC spectrum.