title: KCNK9 imprinting syndrome-further delineation of a possible treatable disorder.
abstract: Patients with KCNK9 imprinting syndrome demonstrate congenital hypotonia, variable cleft palate, normal MRIs and EEGs, delayed development, and feeding problems. Associated facial dysmorphic features include dolichocephaly with bitemporal narrowing, short philtrum, tented upper lip, palatal abnormalities, and small mandible. This disorder maps to chromosomal region 8q24, and it is caused by a specific missense mutation 770G>A in exon 2, replacing glycine at position 236 by arginine (G236R) in the maternal copy of KCNK9 within this locus. KCNK9 (also called TASK3) encodes a member of the two pore- domain potassium channel (K2P) subfamily. This gene is normally imprinted with paternal silencing, thus a mutation in the maternal copy of the gene will result in disease, whereas a mutation in the paternal copy will have no effect. Exome sequencing in four new patients with developmental delay and central hypotonia revealed de novo G236R mutations. Older members of a previously reported Arab-Israeli family have intellectual disability of variable severity, persistent feeding difficulties in infancy with dysphagia of liquids and dysphonia with a muffled voice in early adulthood, generalized hypotonia, weakness of proximal muscles, elongated face with narrow bitemporal diameter, and reduced facial movements. We describe the clinical features in four recently recognized younger patients and compare them with those found in members of the originally reported Arab-Israeli family and suggest this may be a treatable disorder. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California. john.graham@cshs.org.
authors.forename: John M
authors.initials: JM
authors.lastname: Graham
authors.affiliation: Division of Medical Genetics, CHOC Children's Hospital, Orange, California.
authors.forename: Neda
authors.initials: N
authors.lastname: Zadeh
authors.affiliation: KCNK9 Imprinting Syndrome Support Group, Irvine, California.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kelley
authors.affiliation: Department of Paediatric Medicine, KK Women's and Children's Hospital, Singapore.
authors.forename: Ee Shien
authors.initials: ES
authors.lastname: Tan
authors.affiliation: Department of Paediatric Medicine, KK Women's and Children's Hospital, Singapore.
authors.forename: Wendy
authors.initials: W
authors.lastname: Liew
authors.affiliation: Department of Paediatric Medicine, KK Women's and Children's Hospital, Singapore.
authors.forename: Victoria
authors.initials: V
authors.lastname: Tan
authors.affiliation: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.affiliation: Department of Pediatrics, Texas Tech University Health Science Center, Lubbock, Texas.|Medical City Hospital, Dallas, Texas.
authors.forename: Golder N
authors.initials: GN
authors.lastname: Wilson
authors.affiliation: Genetic Institute, Emek Medical Center, Afula, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Sagi-Dain
authors.affiliation: Genetic Institute, Emek Medical Center, Afula, Israel.|Rapapport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
mesh_terms: D019066:Facies; D005260:Female; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics*
chemical_list: C498655:KCNK9 protein, human; D024683:Potassium Channels, Tandem Pore Domain
keywords: Birk-Barel syndrome; K2P subfamily; K2P9.1; KCNK9; TASK3; cleft palate; flufenamic acid; hypotonia; imprinting disorder; intellectual disability; mefenamic acid; personalized medicine; potassium channel disorder