title: Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.
abstract: Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Thomas
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Centre for Translational Omics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Hywel
authors.initials: H
authors.lastname: Williams
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Núria
authors.initials: N
authors.lastname: Setó-Salvia
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Centre for Translational Omics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Dagan
authors.initials: D
authors.lastname: Jenkins
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Sullivan
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Mengrelis
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Miho
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Centre for Translational Omics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Ocaka
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Centre for Translational Omics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Estelle
authors.initials: E
authors.lastname: Chanudet
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Centre for Translational Omics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Chela
authors.initials: C
authors.lastname: James
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Centre for Translational Omics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK; Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lescai
authors.affiliation: Histopathology Department, Great Ormond Street Hospital, London WC1N 3JH, UK.
authors.forename: Glenn
authors.initials: G
authors.lastname: Anderson
authors.affiliation: NE Thames Regional Genetics Laboratory Service, London WC1N 3BH, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morrogh
authors.affiliation: UCL Institute of Neurology, London WC1N 3BG, UK; Department of Clinical Genetics, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Duncan
authors.affiliation: Developmental Biology and Cancer, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Yun Jin
authors.initials: YJ
authors.lastname: Pai
authors.affiliation: Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal; University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, 3000-602 Coimbra, Portugal.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Saraiva
authors.affiliation: Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ramos
authors.affiliation: Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Farren
authors.affiliation: Radiology, Great Ormond Street Hospital, London WC1N 3JH, UK.
authors.forename: Dawn
authors.initials: D
authors.lastname: Saunders
authors.affiliation: Developmental Biology and Cancer, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Vernay
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Straatmaan-Iwanowska
authors.affiliation: Department of Genome Analysis, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, the Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hersheson
authors.affiliation: UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Hurst
authors.affiliation: Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Scott
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Moore
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal. Electronic address: sbsousa@chc.min-saude.pt.
authors.forename: Sérgio B
authors.initials: SB
authors.lastname: Sousa
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: p.stanier@ucl.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
mesh_terms: D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D018389:Codon, Nonsense / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000648:ultrastructure; D053263:Gene Regulatory Networks / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D058305:Sorting Nexins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C000594709:SNX14 protein, human; D058305:Sorting Nexins