Next-generation sequencing identifies novel gene variants and pathways involved in specific language impairment

Abstract

A significant proportion of children suffer from unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. These developmental speech and language disorders are highly heritable and have a substantial impact on society.Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. Here, we performed whole exome sequencing of 43 unrelated probands affected by severe forms of specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to try to shed new light on the aetiology of the disorder. 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 candidate genes 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. When we broadened our scope to all rare and novel variants throughout the exomes, we identified several biological themes that were enriched for such variants, most notably microtubule transport and cytoskeletal regulation.All rights reserved. No reuse allowed without permission.

Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders

“…Full methods on WES sequencing and variant calling are described by Chen et al32. Briefly, for sequencing, the exome was captured by SureSelect Human All Exon version-2 50 Mb kit (Agilent, Santa Clara, CA, USA), sequenced using the SOLiD series 5500xl DNA sequencing platform (Life Technologies, Carlsbad, CA, USA) and called via the standard BWA-GATK pipeline, followed by quality filtering as described by Chen et al 32.…”

“…Briefly, for sequencing, the exome was captured by SureSelect Human All Exon version-2 50 Mb kit (Agilent, Santa Clara, CA, USA), sequenced using the SOLiD series 5500xl DNA sequencing platform (Life Technologies, Carlsbad, CA, USA) and called via the standard BWA-GATK pipeline, followed by quality filtering as described by Chen et al 32. Ethical agreement and informed consent from participants was obtained as described previously33.…”

“…The primary data for the Chen et al32 SLI exome study are deposited at The Language Archive (TLA: https://corpus1.mpi.nl/ds/asv/?0), a public data archive hosted by the Max Planck Institute for Psycholinguistics. Data are stored at the TLA under the node ID: MPI2010433#, and accessible with a persistent identifier: https://hdl.handle.net/1839/00-0000-0000-001E-AD41-2@view.…”

“…Thus, like many other neurodevelopmental disorders, SLI seems to have a heterogeneous set of genetic risk factors contributing to the phenotype. We used WES data from a cohort of 43 affected children with severe SLI32 to demonstrate that it is possible to identify putative causative variants in non-coding 3’UTR regions using NGS datasets. Importantly we showed that variants can have direct functional consequences for gene expression by affecting miRNA binding sites, making them strong candidates for pathogenicity.…”

Language and Cognitive Impairment Associated with a Novel p.Cys63Arg Change in the MED13L Transcriptional Regulator

“…For dyslexia, we relied on Paracchini et al [2016]. For Impairment Associated with Novel p.Cys63Arg Change in MED13L specific language impairment, we chose of Pettigrew et al [2016] and Chen et al [2017]. For language deficits in ASD and schizophrenia, we relied on Benítez-Burraco and and Benítez-Burraco [2016, 2017].…”