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 & 14 others Simon E. Fisher, Dianne F. Newbury, V. Slonims, Ann Clark, Jocelynne Watson, E. Simonoff, A. Pickles, A. Everitt, J. Seckl, H. Cowie, W. Cohen, J. Nasir, D. V M Bishop, Z. Simkin

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

LanguageEnglish
Article numbere1004925
Number of pages24
JournalPLOS Genetics
Volume11
Issue number3
DOIs
Publication statusPublished - 17 Mar 2015

Fingerprint

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

Keywords

  • language
  • chromosomes
  • genomic data
  • variant genotypes

Cite this

Villanueva, P., Nudel, R., Hoischen, A., Fernández, M. A., Simpson, N. H., Gilissen, C., ... Simkin, Z. (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
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. ; Slonims, V. ; Clark, Ann ; Watson, Jocelynne ; Simonoff, E. ; Pickles, A. ; Everitt, A. ; Seckl, J. ; Cowie, H. ; Cohen, W. ; Nasir, J. ; Bishop, D. V M ; Simkin, Z. / 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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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.",
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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, JB, De Barbieri, Z, Fisher, SE, Newbury, DF, Slonims, V, Clark, A, Watson, J, Simonoff, E, Pickles, A, Everitt, A, Seckl, J, Cowie, H, Cohen, W, Nasir, J, Bishop, DVM & Simkin, Z 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

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.; Slonims, V.; Clark, Ann; Watson, Jocelynne; Simonoff, E.; Pickles, A.; Everitt, A.; Seckl, J.; Cowie, H.; Cohen, W.; Nasir, J.; Bishop, D. V M; Simkin, Z.

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

Research output: Contribution to journalArticle

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 - Slonims, V.

AU - Clark, Ann

AU - Watson, Jocelynne

AU - Simonoff, E.

AU - Pickles, A.

AU - Everitt, A.

AU - Seckl, J.

AU - Cowie, H.

AU - Cohen, W.

AU - Nasir, J.

AU - Bishop, D. V M

AU - Simkin, Z.

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.

KW - language

KW - chromosomes

KW - genomic data

KW - variant genotypes

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U2 - 10.1371/journal.pgen.1004925

DO - 10.1371/journal.pgen.1004925

M3 - Article

VL - 11

JO - PLOS Genetics

T2 - PLOS Genetics

JF - PLOS Genetics

SN - 1553-7390

IS - 3

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ER -