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

Villanueva, Pía and Nudel, Ron and Hoischen, Alexander and Fernández, María Angélica and Simpson, Nuala H. and Gilissen, Christian and Reader, Rose H. and Jara, Lillian and Echeverry, Maria Magdalena and Francks, Clyde and Baird, Gillian and Conti-Ramsden, Gina and O’Hare, Anne and Bolton, Patrick F. and Hennessy, Elizabeth R. and Palomino, Hernán and Carvajal-Carmona, Luis and Veltman, Joris A. and Cazier, Jean Baptiste and De Barbieri, Zulema and Fisher, Simon E. and Newbury, Dianne F. and Slonims, V. and Clark, Ann and Watson, Jocelynne and Simonoff, E. and Pickles, A. and Everitt, A. and Seckl, J. and Cowie, H. and Cohen, W. and Nasir, J. and Bishop, D. V M and 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. ISSN 1553-7390

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    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.

    ORCID iDs

    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. ORCID logoORCID: https://orcid.org/0000-0002-1271-9229, Nasir, J., Bishop, D. V M and Simkin, Z.;