A human pleiotropic multiorgan condition caused by deficient Wnt secretion

Guoliang Chai, Emmanuelle Szenker-Ravi, Changuk Chung, Zhen Li, Lu Wang, Muznah Khatoo, Trevor Marshall, Nan Jiang, Xiaoxu Yang, Jennifer McEvoy-Venneri, Valentina Stanley, Paula Anzenberg, Nhi Lang, Vanessa Wazny, Jia Yu, David M. Virshup, Rie Nygaard, Filippo Mancia, Rijad Merdzanic, Maria B.P. TorallesPaula M.L. Pitanga, Ratna D. Puri, Rebecca Hernan, Wendy K. Chung, Aida M. Bertoli-Avella, Nouriya Al-Sannaa, Maha S. Zaki, Karl Willert, Bruno Reversade, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


BACKGROUND Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant “knocked in,” to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring. RESULTS We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development. CONCLUSIONS Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder.
Original languageEnglish (US)
Pages (from-to)1292-1301
Number of pages10
JournalNew England Journal of Medicine
Issue number14
StatePublished - Sep 30 2021
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

  • General Medicine


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