Browsing by Author "Gómez-Puertas, Paulino"
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Item A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 – Review of the literature.(European Journal of Medical Genetics, 2019) Gudmundsson, Sanna; Annéren, Göran; Marcos Alcalde, Íñigo; Wilbe, Maria; Melin, Malin; Gómez-Puertas, Paulino; Bondeson, Marie-LouiseCornelia 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.Item Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome.(International Journal of Molecular Sciences, 2020) Lazo, Pedro A.; García, Juan L.; Gómez-Puertas, Paulino; Marcos Alcalde, Íñigo; Arjona, Cesar; Villarroel, Alvaro; González-Sarmiento, Rogelio; Fons, CarmenComplex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.