Juan L García-Hernández1,2, Luis A Corchete2,3, Íñigo Marcos-Alcalde4,5, Paulino Gómez-Puertas4, Carmen Fons6, Pedro A Lazo7,8. 1. Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, Salamanca, Spain. 2. Instituto de Investigación Biomédica de Salamanca (IBSAL), Departamento de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain. 3. Network Center for Biomedical Research in Cancer (CIBERONC), Salamanca, Spain. 4. Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain. 5. Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain. 6. Neurology Department, Hospital Sant Joan de Déu, Sant Joan de Déu Research Institute, Esplugues de Llobregat, Barcelona and CIBERER, Instituto de Salud Carlos III, Barcelona, Spain. cfons@hsjdbcn.org. 7. Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, Salamanca, Spain. pedro.lazo@csic.es. 8. Instituto de Investigación Biomédica de Salamanca (IBSAL), Departamento de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain. pedro.lazo@csic.es.
Abstract
BACKGROUND: Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. METHODS: To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). RESULTS: The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. CONCLUSIONS: Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.
BACKGROUND: Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. METHODS: To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). RESULTS: The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. CONCLUSIONS: Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.
Authors: Piero Perucca; Ingrid E Scheffer; A Simon Harvey; Paul A James; Sebastian Lunke; Natalie Thorne; Clara Gaff; Brigid M Regan; John A Damiano; Michael S Hildebrand; Samuel F Berkovic; Terence J O'Brien; Patrick Kwan Journal: Epilepsy Res Date: 2017-02-07 Impact factor: 3.045
Authors: Han Chow Chua; Cameron L Noland; Claudia Weidling; Marc Kschonsak; Thomas Clairfeuille; Oskar Ørts Bahlke; Aishat Oluwanifemi Ameen; Zhong Rong Li; Christopher P Arthur; Claudio Ciferri; Stephan Alexander Pless; Jian Payandeh Journal: Nature Date: 2020-07-22 Impact factor: 49.962