title: Five children with deletions of 1p34.3 encompassing AGO1 and AGO3.
abstract: Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.
authors.affiliation: 1] Division of Genetic Medicine, University of Washington, Seattle, WA, USA [2] Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Mari J
authors.initials: MJ
authors.lastname: Tokita
authors.affiliation: 1] Division of Genetic Medicine, University of Washington, Seattle, WA, USA [2] Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Penny M
authors.initials: PM
authors.lastname: Chow
authors.affiliation: 1] Division of Genetic Medicine, University of Washington, Seattle, WA, USA [2] Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Ghayda
authors.initials: G
authors.lastname: Mirzaa
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dikow
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Maas
authors.affiliation: Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
authors.affiliation: Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Lynette S
authors.initials: LS
authors.lastname: Penney
authors.affiliation: School of Specialization in Childhood Neurology and Psychiatry, University of Perugia, Perugia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mazzotta
authors.affiliation: Mendel Laboratory, IRCSS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bernardini
authors.affiliation: The Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Calambrone (Pisa), Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Filippi
authors.affiliation: The Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Calambrone (Pisa), Italy.
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.affiliation: Medical Genetics Unit, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Donti
authors.affiliation: 1] Division of Genetic Medicine, University of Washington, Seattle, WA, USA [2] Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Earl
authors.affiliation: Medical Genetics Unit, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Prontera
mesh_terms: D000293:Adolescent; D060565:Argonaute Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D039642:Eukaryotic Initiation Factors / Q000235:genetics*; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics*; D013577:Syndrome
chemical_list: C115848:AGO1 protein, human; C517143:AGO3 protein, human; D060565:Argonaute Proteins; D039642:Eukaryotic Initiation Factors