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

Abstract

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.

Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

“…Written informed consent for the genomic study was obtained from both parents. Research protocol and consent forms were approved by the Institutional Review Boards of Hospital Universitario de Salamanca-Centro de Investigación del Cancer as reported in a previous publication [ 17 ].…”

“…Therefore, it is likely that heterogeneity in neurological phenotypes can also be a consequence of alternative combinations of genetic changes in genes associated to cellular functions that are involved in the phenotype and constitute the individual variome [ 8 , 9 ]. Therefore, we tested this hypothesis by searching for CNV variome differences among the four family members of a complex case of a child, as test case, that presented a developmental and epileptic encephalopathy of neonatal onset that has a novel KCNQ2 mutation resulting from a partial KCNQ2 exon 7 duplication that impairs its inhibitory signal [ 17 ] and to determine if the proband has a CNV pattern associated to neuronal functions. However, the complexity of the neurological syndrome suggested that, although this mutation is necessary, there has to be additional cooperating genetic alterations.…”

“…However, the complexity of the neurological syndrome suggested that, although this mutation is necessary, there has to be additional cooperating genetic alterations. We have approached the identification of the underlying genetic problem by studying CNV alterations and their association to genes whose function can contribute to the neuropathological phenotype reported in the proband and absent in the family [ 17 ], as an alternative approach to searching for common variants among unrelated individuals with similar phenotypes. Complex neurodevelopmental delay and epileptic phenotypes might be the result of de novo combination of CNV alterations in genes associated to neurological functions that contribute to the patient syndrome and determine its pathogenic mechanism.…”

Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

“…Because the WES study did not identify any additional gene variant or mutant associated to the pathology, in addition to the known KCNQ2 exon 7 partial duplication [17], and in order to detect additional cooperating gene alterations that contribute to the pathogenesis of the patient complex neurological syndrome, the genome of the proband and family members was further studied by SNP microarrays to detect CNVs.…”

“…Intronic alterations can alter the processing of the RNA or its stability. Calcium-dependent celladhesion protein primarily expressed in the developing brain [73,74] PCDH19 pathogenic variants and CNV in epilepsy [38,[73][74][75][76][77][78] Next, we performed a search for a pathogenic association of all the genes comprised within these CNVs detected in the patient, by either SNP microarray or WES, and correlated their functions with different aspects of the clinical phenotype [17]. For this aim the VarElect program was used [22].…”