RAD21 was reported in relation to autosomal dominant Cornelia de Lange syndrome (CdLS) as early as 2012 (Deardorff et al., PMID: 22633399). CdLS is characterized by phenotypes including intellectual disability, autism, developmental delay, characteristic facial dysmorphisms, short stature, and other skeletal anomalies. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven probands harboring missense and truncating variants as well as an in-frame deletion are documented here, although additional cases have been reported in the literature (PMIDs: 22633399, 24378232, 27882533, 27620904, 30716475, 30125677). While the majority of cases occurred de novo, variants in RAD21 segregated with CdLS-like features in 3 additional individuals in 1 family, although their phenotypes were considered too mild by the authors to be diagnosed with classical CdLS (PMID: 27882533). Of note, RAD21 has been associated with a milder form of CdLS compared to other genes such as NIPBL, HDAC8, and SMC1A. This gene-disease association is supported by animal models and a rescue experiment (PMIDs: 17567667, 25378554). In summary, RAD21 is definitively associated with autosomal dominant Cornelia de Lange syndrome.
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