Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment
A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but mu...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Research
2017
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| _version_ | 1797068397213646848 |
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| author | Chen, XS Reader, RH Hoischen, A Veltman, JA Simpson, NH Francks, C Newbury, DF Fisher, SE |
| author_facet | Chen, XS Reader, RH Hoischen, A Veltman, JA Simpson, NH Francks, C Newbury, DF Fisher, SE |
| author_sort | Chen, XS |
| collection | OXFORD |
| description | A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation. |
| first_indexed | 2024-03-06T22:10:11Z |
| format | Journal article |
| id | oxford-uuid:518c8ba0-aec3-460d-acfd-60e802ee7a59 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:10:11Z |
| publishDate | 2017 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:518c8ba0-aec3-460d-acfd-60e802ee7a592022-03-26T16:20:09ZNext-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairmentJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:518c8ba0-aec3-460d-acfd-60e802ee7a59EnglishSymplectic Elements at OxfordNature Research2017Chen, XSReader, RHHoischen, AVeltman, JASimpson, NHFrancks, CNewbury, DFFisher, SEA significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation. |
| spellingShingle | Chen, XS Reader, RH Hoischen, A Veltman, JA Simpson, NH Francks, C Newbury, DF Fisher, SE Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment |
| title | Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment |
| title_full | Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment |
| title_fullStr | Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment |
| title_full_unstemmed | Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment |
| title_short | Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment |
| title_sort | next generation dna sequencing identifies novel gene variants and pathways involved in specific language impairment |
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