Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/21368
Title: Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations.
Austin Authors: Cameron, Jillian M ;Maljevic, Snezana;Nair, Umesh;Aung, Ye Htet;Cogné, Benjamin;Bézieau, Stéphane;Blair, Edward;Isidor, Bertrand;Zweier, Christiane;Reis, André;Koenig, Mary Kay;Maarup, Timothy;Sarco, Dean;Afenjar, Alexandra;Huq, A H M Mahbubul;Kukolich, Mary;Billette de Villemeur, Thierry;Nava, Caroline;Héron, Bénédicte;Petrou, Steven;Berkovic, Samuel F 
Affiliation: Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
Oxford Centre for Genomic Medicine, ACE Building, Nuffield Orthopaedic Centre, Windmill Road, Oxford, United Kingdom
Service de génétique medicale, Centre Hospitalier, Université de Nantes, Nantes, France
L'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia
Centre de référence des malformations et maladies congénitales du cervelet, Département de génétique médicale, Sorbonne Université, GRC ConCer-LD, AP-HP, Hôpital Armand Trousseau, F-75012, Paris, France
Sorbonne Universite, GRC ConCer-LD, Neuropédiatrie, Trousseau Hospital, AP-HP, Inserm U1141, Paris, France
Département de Génétique, Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, AP-HP, Hôpital de la Pitié Salpêtrière, F-75013, Paris, France
Sorbonne Université, GRC N°19, Service de Neuropediatrie, Hôpital Trousseau La Roche Guyon (APHP), La Roche Guyon, France
Department of Paediatrics, Division of Child & Adolescent Neurology, The University of Texas McGovern Medical School, Houston, Texas
Southern California Permanente Medical Group, Pasadena, California
Wayne State University, Detroit, Michigan
Genetics Department, Cook Children's Health Care System, Fort Worth, Texas
Issue Date: Jul-2019
metadata.dc.date: 2019-07-01
Publication information: Annals of clinical and translational neurology 2019; 6(7): 1263-1272
Abstract: To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy-causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype-phenotype-physiological correlations. Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole-exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the Kv 3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two-electrode voltage clamping were used. Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole-cell current, but no dominant-negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole-cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance. These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21368
DOI: 10.1002/acn3.50822
ORCID: 0000-0002-2175-5977
0000-0003-4580-841X
PubMed URL: 31353855
Type: Journal Article
Subjects: Encephalopathy
KCNC1
epilepsy
Appears in Collections:Journal articles

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