A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 – Review of the literature.
Author: Gudmundsson, Sanna; Annéren, Göran; Marcos Alcalde, Íñigo; Wilbe, Maria; Melin, Malin; Gómez-Puertas, Paulino; Bondeson, Marie-Louise
Abstract: Cornelia 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.
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