ZEB2 – Mowat-Wilson syndrome

Mowat-Wilson syndrome (MWS) is an autosomal dominant neurodevelopmental disorder caused by heterozygous mutations or deletions in the ZEB2 gene and characterized by moderate-to-severe intellectual disability, distinctive facial gestalt, microcephaly, seizures, Hirschsprung disease, agenesis of the corpus callosum and congenital heart defects (PMID:17958891).

ZEB2 encodes the Smad-interacting protein-1 (SIP1), a transcriptional corepressor that modulates TGF-β signaling during neural crest and central nervous system development. Over 350 patients carrying predominantly de novo loss-of-function variants—mainly nonsense and frameshift mutations clustering in exon 8, such as c.2761C>T (p.Arg921Ter)—have been reported, underpinning a high penetrance clinical profile (PMID:36345475; PMID:17203459).

Genetic evidence demonstrates de novo occurrence in nearly all sporadic cases, with rare familial recurrence due to parental germ-line mosaicism. Segregation analyses describe at least 5 additional affected relatives across multiple families, supporting an autosomal dominant inheritance with low recurrence risk (PMID:16088920). The breadth and consistency of these findings yield a Definitive ClinGen gene–disease association.

Extensive variant spectrum includes over 180 distinct truncating mutations (nonsense, frameshift, splice-site) and large deletions or duplications of ZEB2, all leading to haploinsufficiency. The recurrent c.2761C>T (p.Arg921Ter) variant typifies the mutational hotspot in exon 8 and serves as a molecular diagnostic marker in many cohorts.

Functional models in zebrafish and mice confirm that ZEB2 haploinsufficiency disrupts neural crest cell specification, corpus callosum formation, and pain perception pathways, recapitulating key features of MWS. Rescue experiments and in vitro assays align with the human phenotype, providing Moderate functional evidence for pathogenicity (PMID:15006694; PMID:26319231).

In summary, the combination of extensive genetic data and concordant experimental models establishes a Definitive ZEB2–Mowat-Wilson syndrome association. Clinical testing for ZEB2 mutations—including sequencing of exon 8 and dosage analysis—should be prioritized for individuals with characteristic facial features, intellectual disability, and multi-system congenital anomalies to facilitate early diagnosis and management.

References

• Orphanet journal of rare diseases • 2007 • Mowat-Wilson syndrome. PMID:17958891
• Human mutation • 2007 • ZFHX1B mutations in patients with Mowat-Wilson syndrome. PMID:17203459
• American journal of medical genetics. Part A • 2005 • Recurrence of Mowat-Wilson syndrome in siblings with the same proven mutation. PMID:16088920
• Neurobiology of disease • 2004 • Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the “Mowat-Wilson” syndrome. PMID:15006694
• Human molecular genetics • 2015 • De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome. PMID:26319231
• Pharmacogenomics and personalized medicine • 2022 • Mowat-Wilson Syndrome as a Differential Diagnosis in Patients with Congenital Heart Defects and Dysmorphic Facies. PMID:36345475

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