title: Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations.
abstract: Mutations in the KCNA1 gene are known to cause episodic ataxia/myokymia syndrome type 1 (EA1). Here, we describe two families with unique presentations who were enrolled in an IRB-approved study, extensively phenotyped, and whole exome sequencing (WES) performed. Family 1 had a diagnosis of isolated cataplexy triggered by sudden physical exertion in multiple affected individuals with heterogeneous neurological findings. All enrolled affected members carried a KCNA1 c.941T>C (p.I314T) mutation. Family 2 had an 8-year-old patient with muscle spasms with rigidity for whom WES revealed a previously reported heterozygous missense mutation in KCNA1 c.677C>G (p.T226R), confirming the diagnosis of EA1 without ataxia. WES identified variants in KCNA1 that explain both phenotypes expanding the phenotypic spectrum of diseases associated with mutations of this gene. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. This is an example of the power of genomic approaches to identify pathogenic mutations in unsuspected genes responsible for heterogeneous diseases.
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA. catherine.brownstein@childrens.harvard.edu.|The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA. catherine.brownstein@childrens.harvard.edu.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Brownstein
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.|The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Rodan
authors.affiliation: Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, USA.|Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Jiahai
authors.initials: J
authors.lastname: Shi
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.|The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Towne
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.|The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Pelletier
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.|Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.|The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Siqi
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rosenberg
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Urion
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Picker
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
authors.forename: Wen-Hann
authors.initials: WH
authors.lastname: Tan
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA. pagrawal@enders.tch.harvard.edu.|Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA. pagrawal@enders.tch.harvard.edu.|The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA. pagrawal@enders.tch.harvard.edu.
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Agrawal
mesh_terms: D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000235:genetics*; D002385:Cataplexy / Q000235:genetics*; D002648:Child; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D020385:Myokymia / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: C496946:KCNA1 protein, human; D051662:Kv1.1 Potassium Channel
keywords: Cataplexy; Episodic ataxia; Hypertonia; KCNA1; Whole exome sequencing