Mowat-Wilson syndrome

Classic Mowat-Wilson syndrome is caused by germline pathogenic variants in ZEB2 (2q22.3). Variants found in affected individuals comprise sequence variants (~84%), gene-targeted deletions or chromosomal microdeletions involving ZEB2 (~15%) and chromosome rearrangements disrupting ZEB2 (~1%). ZEB2 encodes a two-handed zinc-finger/homeodomain transcription factor that interacts with SMAD proteins to repress transcription within TGF-β signalling and contributes to neural crest development, cortical neuron differentiation and SOX10-dependent formation of the enteric nervous system; disease results from haploinsufficiency.

Mowat-Wilson syndrome is inherited in an autosomal dominant manner. Most affected individuals represent simplex cases; the recurrence risk to siblings of a proband is approximately 2%, reflecting the possibility of parental gonadal mosaicism. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Main differential diagnoses include:

• : severe intellectual disability and episodic hyperventilation and/or breath-holding while awake; TCF4.
• : absent speech with a happy demeanor; UBE3A.
• : Hirschsprung disease, cleft palate and ocular coloboma; KIF1BP

• Establishing the molecular diagnosis, which clarifies the underlying genetic cause and informs prognosis and clinical decision-making.
• Enabling specific and individualised surveillance addressing the recognised neurological, cardiac, gastrointestinal and genitourinary manifestations, a prerequisite for targeted medical care decided by the treating physicians in consultation with the affected individual and their family.
• Identifying at-risk family members, in whom predictive testing can be considered once the familial pathogenic variant has been identified.

• Adam MP, Conta J, Bean LJH. Classic Mowat-Wilson Syndrome. 2007 Mar 28. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301585. Available from:
• Cordelli DM, Di Pisa V, Fetta A, Garavelli L, Maltoni L, Soliani L, et al. Neurological Phenotype of Mowat-Wilson Syndrome. Genes. 2021;12(7). doi: 10.3390/genes12070982. PMID: . PMCID: PMC8305916.
• St Peter C, Hossain WA, Lovell S, Rafi SK, Butler MG. Mowat-Wilson Syndrome: Case Report and Review of ZEB2 Gene Variant Types, Protein Defects and Molecular Interactions. International journal of molecular sciences. 2024;25(5). doi: 10.3390/ijms25052838. PMID: . PMCID: PMC10932183.