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PLoS Genet. 2015 Mar 17;11(3):e1004925. doi: 10.1371/journal.pgen.1004925. eCollection 2015 Mar.

Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment.

Author information

1
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.
2
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
3
Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
4
School of Speech and Hearing Therapy, Faculty of Medicine, University of Chile, Santiago, Chile.
5
Human Genetics Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.
6
Grupo de Citogenetica, Filogenia y Evolucion de las Poblaciones, Facultades de Ciencias y de Ciencias de la Salud, Universidad del Tolima, Ibague, Colombia.
7
Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
8
Newcomen Centre, the Evelina Children's Hospital, London, United Kingdom.
9
School of Psychological Sciences, University of Manchester, Manchester, United Kingdom.
10
Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, United Kingdom.
11
Departments of Child & Adolescent Psychiatry & Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.
12
University Child Health and DMDE, University of Aberdeen, Aberdeen, United Kingdom.
13
Department of Child and Dental Maxillary Orthopedics, Faculty of Dentistry, University of Chile, Santiago, Chile.
14
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.
15
Department of Oncology, University of Oxford, Oxford, United Kingdom; Centre for Computational Biology, University of Birmingham, Edgbaston, United Kingdom.
16
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; St Johns College, University of Oxford, Oxford, United Kingdom.

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.

PMID:
25781923
PMCID:
PMC4363375
DOI:
10.1371/journal.pgen.1004925
[Indexed for MEDLINE]
Free PMC Article

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