title: Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment.
abstract: Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10-4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.
authors.affiliation: Human Genetics Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile; School of Speech and Hearing Therapy, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Child and Dental Maxillary Orthopedics, Faculty of Dentistry, University of Chile, Santiago, Chile; Doctoral Program of Psychology, Graduate School, University of Granada, Granada, Spain.
authors.forename: Pía
authors.initials: P
authors.lastname: Villanueva
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Ron
authors.initials: R
authors.lastname: Nudel
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: School of Speech and Hearing Therapy, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: María Angélica
authors.initials: MA
authors.lastname: Fernández
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Nuala H
authors.initials: NH
authors.lastname: Simpson
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Rose H
authors.initials: RH
authors.lastname: Reader
authors.affiliation: Human Genetics Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Lillian
authors.initials: L
authors.lastname: Jara
authors.affiliation: Grupo de Citogenetica, Filogenia y Evolucion de las Poblaciones, Facultades de Ciencias y de Ciencias de la Salud, Universidad del Tolima, Ibague, Colombia.
authors.forename: María Magdalena
authors.initials: MM
authors.lastname: Echeverry
authors.forename: Maria Magdalena
authors.initials: MM
authors.lastname: Echeverry
authors.affiliation: Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
authors.forename: Clyde
authors.initials: C
authors.lastname: Francks
authors.affiliation: Newcomen Centre, the Evelina Children's Hospital, London, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Baird
authors.affiliation: School of Psychological Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Gina
authors.initials: G
authors.lastname: Conti-Ramsden
authors.affiliation: Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Hare
authors.affiliation: Departments of Child & Adolescent Psychiatry & Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Bolton
authors.affiliation: University Child Health and DMDE, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hennessy
authors.affiliation: Department of Child and Dental Maxillary Orthopedics, Faculty of Dentistry, University of Chile, Santiago, Chile.
authors.forename: Hernán
authors.initials: H
authors.lastname: Palomino
authors.affiliation: Grupo de Citogenetica, Filogenia y Evolucion de las Poblaciones, Facultades de Ciencias y de Ciencias de la Salud, Universidad del Tolima, Ibague, Colombia; UC Davis Genome Center, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Luis
authors.initials: L
authors.lastname: Carvajal-Carmona
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Oncology, University of Oxford, Oxford, United Kingdom; Centre for Computational Biology, University of Birmingham, Edgbaston, United Kingdom.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.affiliation: School of Speech and Hearing Therapy, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Zulema
authors.initials: Z
authors.lastname: De Barbieri
authors.affiliation: Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; St Johns College, University of Oxford, Oxford, United Kingdom.
authors.forename: Dianne F
authors.initials: DF
authors.lastname: Newbury
mesh_terms: D001072:Apraxias / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C508936:NFXL1 protein, human