ZEB2 was first reported in relation to autosomal dominant Mowat-Wilson syndrome in 2001 (Wakamatsu et al., PMID: 11279515; Cacheux et al., PMID: 11448942). Mowat-Wilson syndrome is characterized by moderate-to-severe intellectual disability, typical dysmorphic features, microcephaly and seizures. Congenital anomalies, including Hirschsprung disease, congenital heart defects, genitourinary abnormalities, agenesis of the corpus callosum, and short stature, are common.
Over 200 variants (missense, nonsense, frameshift, splicing, small and gross deletions, gross insertions/duplications, and complex rearrangements) have been reported in the literature. Eight variants (frameshift, nonsense and missense) that have been reported in eight probands in three publications (PMIDs: 9719364, 16053902, 16688751) are included in this curation. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by mouse models and functional alteration in non-patient cells.
In summary, there is definitive evidence supporting the relationship between ZEB2 and autosomal dominant Mowat-Wilson syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 23, 2018 (SOP Version 5).
The ZEB2 gene has been associated with autosomal dominant Mowat-Wilson syndrome using the ClinGen Clinical Validity Framework as of 5/22/2018. The association was made using case-level data only. While over 200 variants (missense, nonsense, splicing, small deletions, small insertions, small indels, gross deletions, gross insertions/duplications, and complex rearrangements) have been reported in humans in literature, 8 variants were scored in this curation to max out evidence. ZEB2 was first associated with this disease in humans as early as 1998 (Mowat et al.). The gene-disease association is supported by multiple mouse models and expression studies. Again, additional evidence exists beyond what was curated, however the Definitive classification was already reached. In summary, ZEB2 is definitively associated with autosomal dominant Mowat-Wilson syndrome.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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