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Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome

2020; Multidisciplinary Digital Publishing Institute; Volume: 21; Issue: 12 Linguagem: Inglês

10.3390/ijms21124447

1661-6596

Pedro A. Lazo, Juan Luis Garcı́a, Paulino Gómez‐Puertas, Íñigo Marcos‐Alcalde, César Arjona, Álvaro Villarroel, Rogelio González‐Sarmiento, Carmen Fons,

Ion channel regulation and function

Complex 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.