Gudmundsson, SannaAnnéren, GöranMarcos Alcalde, ÍñigoWilbe, MariaMelin, MalinGómez-Puertas, PaulinoBondeson, Marie-Louise2020-10-052020-10-0520191769-7212http://hdl.handle.net/10641/1986Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a mutation in one of five CdLS associated cohesin proteins. Around 500 mutations have been identified to cause CdLS, however only eight different alterations are identified in RAD21, encoding the RAD21 cohesin protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15- month-old boy presenting with developmental delay, distinct CdLS facial features, gastrointestinal reflux in early infancy, testis retention fetal pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del; p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Functional assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a novel RAD21 p.(Glu592del) variant that expands the clinical description of CdLS type 4 and validate the pathogenicity of the variant by in silico structural modeling that displayed disturbed RAD21-SMC1A interface.engAtribución-NoComercial-SinDerivadas 3.0 Españahttp://creativecommons.org/licenses/by-nc-nd/3.0/es/RAD21Cornelia de Lange syndrome type 4Cohesin proteinCohesin complexjournal articleopen access10.1016/j.ejmg.2018.08.007