Submission Details

The MAB21L2 gene is located on chromosome 4 at 4q31.3 and is similar to C. elegans MAB-21 cell fate-determining gene, a downstream target of transforming growth factor-beta signaling. It is thought that this gene may be involved in neural development. MAB21L2 was first reported in relation to autosomal dominant Microphthalmia/Coloboma-Rhizomelic Dysplasia syndrome in 2014 (Rainger et al., PMID: 24906020). Other ophthalmic abnormalities reported in affected probands include anophthalmia, cataracts, and microcornea. Skeletal features reported in affected probands include recurrent dislocation of the patella, syndactyly, and joint contractures. The condition is also associated with intellectual disability/autism. Phenotypic variability is reported. Four missense, three nonsense variants, and one start loss variant that have been reported in nine probands in six publications (PMIDs: 34008892, 32830442, 29450879, 24906020, 25719200, 32737437) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function but some pathogenic variants have been shown to have an increase in stability/activating effect. Residues 49-52 of MAB21L2 appear to be particularly important to the protein function. This gene-disease relationship is also supported by experimental evidence including a mouse model, a zebrafish model, and expression evidence (PMIDs: 30375740, 25719200, 30073347). The mutant mice show high phenotypic specificity with eye and skeletal anomalies. In summary, there is definitive evidence supporting the relationship between MAB21L2 and autosomal dominant Microphthalmia/Coloboma-Rhizomelic Dysplasia 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 Syndromic Disorders GCEP on the meeting date September 6, 2023 (SOP Version 9).