Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment

Pía Villanueva, Ron Nudel, Alexander Hoischen, María Angélica Fernández, Nuala H Simpson, Christian Gilissen, Rose H Reader, Lillian Jara, Maria Magdalena Echeverry, Clyde Francks, Gillian Baird, Gina Conti-Ramsden, Anne O'Hare, Patrick F Bolton, Elizabeth R Hennessy, Hernán Palomino, Luis Carvajal-Carmona, Joris A Veltman, Jean-Baptiste Cazier, Zulema De Barbieri & 3 others Simon E Fisher, Dianne F Newbury, SLI Consortium

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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.

Original languageEnglish
Article numbere1004925
Number of pages24
JournalPLoS Genetics
Volume11
Issue number3
Early online date17 Mar 2015
DOIs
Publication statusPublished - 17 Mar 2015

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Exome
isolated population
Language
Population
Genetic Techniques
Chile
Genetic Models
founder effect
Intelligence
Islands
Gene Frequency
molecular genetics
gene frequency
Molecular Biology
allele
incidence
gene
Incidence

Cite this

Villanueva, P., Nudel, R., Hoischen, A., Fernández, M. A., Simpson, N. H., Gilissen, C., ... SLI Consortium (2015). Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment. PLoS Genetics, 11(3), [e1004925]. https://doi.org/10.1371/journal.pgen.1004925

Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment. / Villanueva, Pía; Nudel, Ron; Hoischen, Alexander; Fernández, María Angélica; Simpson, Nuala H; Gilissen, Christian; Reader, Rose H; Jara, Lillian; Echeverry, Maria Magdalena; Francks, Clyde; Baird, Gillian; Conti-Ramsden, Gina; O'Hare, Anne; Bolton, Patrick F; Hennessy, Elizabeth R; Palomino, Hernán; Carvajal-Carmona, Luis; Veltman, Joris A; Cazier, Jean-Baptiste; De Barbieri, Zulema; Fisher, Simon E; Newbury, Dianne F; SLI Consortium.

In: PLoS Genetics, Vol. 11, No. 3, e1004925, 17.03.2015.

Research output: Contribution to journalArticle

Villanueva, P, Nudel, R, Hoischen, A, Fernández, MA, Simpson, NH, Gilissen, C, Reader, RH, Jara, L, Echeverry, MM, Francks, C, Baird, G, Conti-Ramsden, G, O'Hare, A, Bolton, PF, Hennessy, ER, Palomino, H, Carvajal-Carmona, L, Veltman, JA, Cazier, J-B, De Barbieri, Z, Fisher, SE, Newbury, DF & SLI Consortium 2015, 'Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment', PLoS Genetics, vol. 11, no. 3, e1004925. https://doi.org/10.1371/journal.pgen.1004925
Villanueva, Pía ; Nudel, Ron ; Hoischen, Alexander ; Fernández, María Angélica ; Simpson, Nuala H ; Gilissen, Christian ; Reader, Rose H ; Jara, Lillian ; Echeverry, Maria Magdalena ; Francks, Clyde ; Baird, Gillian ; Conti-Ramsden, Gina ; O'Hare, Anne ; Bolton, Patrick F ; Hennessy, Elizabeth R ; Palomino, Hernán ; Carvajal-Carmona, Luis ; Veltman, Joris A ; Cazier, Jean-Baptiste ; De Barbieri, Zulema ; Fisher, Simon E ; Newbury, Dianne F ; SLI Consortium. / Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment. In: PLoS Genetics. 2015 ; Vol. 11, No. 3.
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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.",
author = "P{\'i}a Villanueva and Ron Nudel and Alexander Hoischen and Fern{\'a}ndez, {Mar{\'i}a Ang{\'e}lica} and Simpson, {Nuala H} and Christian Gilissen and Reader, {Rose H} and Lillian Jara and Echeverry, {Maria Magdalena} and Clyde Francks and Gillian Baird and Gina Conti-Ramsden and Anne O'Hare and Bolton, {Patrick F} and Hennessy, {Elizabeth R} and Hern{\'a}n Palomino and Luis Carvajal-Carmona and Veltman, {Joris A} and Jean-Baptiste Cazier and {De Barbieri}, Zulema and Fisher, {Simon E} and Newbury, {Dianne F} and {SLI Consortium}",
note = "Copyright: {\circledC} 2015 Villanueva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: Data used in this paper come from a small and well-defined population. To protect the identity of individuals, these confidential data are not publically available. Data are available from the University of Chile Ethics Committee for researchers who meet the criteria for access to confidential data. Acknowledgments: We would like to thank all the families, professionals and individuals who participated in this research. In particular we are extremely grateful to the inhabitants of Robinson Crusoe Island who have agreed to participate in this study. We would also like to thank Mr. Felipe Paredes, the mayor of the Ilustre Municipalidad de Juan Fern{\'a}ndez for his infinite assistance and patience in the development of this research. Also to the authorities of schools of medicine and dentistry for giving us the necessary permits to travel to the island of Juan Fernandez. We are very grateful to all members of the SLI Consortium for their contributions to this work: V. Slonims (Newcomen Centre, Evelina Children’s Hospital, London, UK), A. Clark, J Watson (Speech and Hearing Sciences, Queen Margaret University, Edinburgh, UK), E. Simonoff, A Pickles (King’s College London, Institute of Psychiatry); A. Everitt (University Child Health and DMDE, University of Aberdeen); J. Seckl (Molecular Medicine Centre, University of Edinburgh); H. Cowie (Department of Speech and Language Therapy, Royal Hospital for Sick Children, Edinburgh); W. Cohen (Psychological Sciences and Health, University of Strathclyde); J. Nasir (Division of Biomedical Sciences, St George’s University of London); D.V.M. Bishop (Department of Experimental Psychology, University of Oxford); Z. Simkin (School of Psychological Sciences, University of Manchester). Funding: DFN and the work of the Newbury lab are funded by an MRC Career Development Fellow and a Junior Research Fellow at St John’s College, University of Oxford. The work of the Newbury lab is funded by the Medical Research Council [G1000569/1]. The Robinson Crusoe project is funded by the Medical Research Council [MR/J003719/1]. The collection of DNA samples and characterisation of the Robinson Crusoe population was funded by Vicerrector{\'i}a de Investigaci{\'o}n, Universidad de Chile (www.uchile.cl), UCHILE DID TNAC 01-02/01, UCHILE DI MULT 05-05/02 grants. RN is funded by a University of Oxford Nuffield Department of Medicine Prize Studentship. SEF and CF are supported by the Max Planck Society, who also funded the exome sequencing. LCC and MME receive funding from the European Union FP7 CHIBCHA Consortium, GSK Oncology (Ethnic Research Initiative), Colciencias, Cancer Research UK and Universidad del Tolima. LCC receives funding from the University of California Davis, The V Foundation for Cancer Research, and The National Institute On Aging (award number P30AG043097) and The National Cancer Institute (Award number K12CA138464) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The collection of the SLIC samples was supported by the Wellcome Trust (060774and 076566). PFB is supported by a National Institute of Health Research (UK) Senior Investigator award and the Biomedical Research Centre in Mental Health at the South London & Maudsley NHS Trust Hospital, London. The High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics is funded by the Wellcome Trust [090532/Z/09/Z] and the MRC [G0900747 91070]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",
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TY - JOUR

T1 - Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment

AU - Villanueva, Pía

AU - Nudel, Ron

AU - Hoischen, Alexander

AU - Fernández, María Angélica

AU - Simpson, Nuala H

AU - Gilissen, Christian

AU - Reader, Rose H

AU - Jara, Lillian

AU - Echeverry, Maria Magdalena

AU - Francks, Clyde

AU - Baird, Gillian

AU - Conti-Ramsden, Gina

AU - O'Hare, Anne

AU - Bolton, Patrick F

AU - Hennessy, Elizabeth R

AU - Palomino, Hernán

AU - Carvajal-Carmona, Luis

AU - Veltman, Joris A

AU - Cazier, Jean-Baptiste

AU - De Barbieri, Zulema

AU - Fisher, Simon E

AU - Newbury, Dianne F

AU - SLI Consortium

N1 - Copyright: © 2015 Villanueva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: Data used in this paper come from a small and well-defined population. To protect the identity of individuals, these confidential data are not publically available. Data are available from the University of Chile Ethics Committee for researchers who meet the criteria for access to confidential data. Acknowledgments: We would like to thank all the families, professionals and individuals who participated in this research. In particular we are extremely grateful to the inhabitants of Robinson Crusoe Island who have agreed to participate in this study. We would also like to thank Mr. Felipe Paredes, the mayor of the Ilustre Municipalidad de Juan Fernández for his infinite assistance and patience in the development of this research. Also to the authorities of schools of medicine and dentistry for giving us the necessary permits to travel to the island of Juan Fernandez. We are very grateful to all members of the SLI Consortium for their contributions to this work: V. Slonims (Newcomen Centre, Evelina Children’s Hospital, London, UK), A. Clark, J Watson (Speech and Hearing Sciences, Queen Margaret University, Edinburgh, UK), E. Simonoff, A Pickles (King’s College London, Institute of Psychiatry); A. Everitt (University Child Health and DMDE, University of Aberdeen); J. Seckl (Molecular Medicine Centre, University of Edinburgh); H. Cowie (Department of Speech and Language Therapy, Royal Hospital for Sick Children, Edinburgh); W. Cohen (Psychological Sciences and Health, University of Strathclyde); J. Nasir (Division of Biomedical Sciences, St George’s University of London); D.V.M. Bishop (Department of Experimental Psychology, University of Oxford); Z. Simkin (School of Psychological Sciences, University of Manchester). Funding: DFN and the work of the Newbury lab are funded by an MRC Career Development Fellow and a Junior Research Fellow at St John’s College, University of Oxford. The work of the Newbury lab is funded by the Medical Research Council [G1000569/1]. The Robinson Crusoe project is funded by the Medical Research Council [MR/J003719/1]. The collection of DNA samples and characterisation of the Robinson Crusoe population was funded by Vicerrectoría de Investigación, Universidad de Chile (www.uchile.cl), UCHILE DID TNAC 01-02/01, UCHILE DI MULT 05-05/02 grants. RN is funded by a University of Oxford Nuffield Department of Medicine Prize Studentship. SEF and CF are supported by the Max Planck Society, who also funded the exome sequencing. LCC and MME receive funding from the European Union FP7 CHIBCHA Consortium, GSK Oncology (Ethnic Research Initiative), Colciencias, Cancer Research UK and Universidad del Tolima. LCC receives funding from the University of California Davis, The V Foundation for Cancer Research, and The National Institute On Aging (award number P30AG043097) and The National Cancer Institute (Award number K12CA138464) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The collection of the SLIC samples was supported by the Wellcome Trust (060774and 076566). PFB is supported by a National Institute of Health Research (UK) Senior Investigator award and the Biomedical Research Centre in Mental Health at the South London & Maudsley NHS Trust Hospital, London. The High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics is funded by the Wellcome Trust [090532/Z/09/Z] and the MRC [G0900747 91070]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2015/3/17

Y1 - 2015/3/17

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1004925

DO - 10.1371/journal.pgen.1004925

M3 - Article

VL - 11

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 3

M1 - e1004925

ER -