Genomic sequencing of a dyslexia susceptibility haplotype encompassing ROBO1 / Satu MASSINEN in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.4 Titre : Genomic sequencing of a dyslexia susceptibility haplotype encompassing ROBO1 Type de document : texte imprimé Auteurs : Satu MASSINEN, Auteur ; Jing WANG, Auteur ; Krista LAIVUORI, Auteur ; Andrea BIEDER, Auteur ; Isabel TAPIA PAEZ, Auteur ; Hong JIAO, Auteur ; Juha KERE, Auteur Article en page(s) : p.4 Langues : Anglais (eng) Mots-clés : Dyslexia  Robo1  Whole genome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: The DYX5 locus for developmental dyslexia was mapped to chromosome 3 by linkage study of a large Finnish family, and later, roundabout guidance receptor 1 (ROBO1) was implicated as a candidate gene at DYX5 with suppressed expression from the segregating rare haplotype. A functional magnetoencephalographic study of several family members revealed abnormal auditory processing of interaural interaction, supporting a defect in midline crossing of auditory pathways. In the current study, we have characterized genetic variation in the broad ROBO1 gene region in the DYX5-linked family, aiming to identify variants that would increase our understanding of the altered expression of ROBO1. METHODS: We have used a whole genome sequencing strategy on a pooled sample of 19 individuals in combination with two individually sequenced genomes. The discovered genetic variants were annotated and filtered. Subsequently, the most interesting variants were functionally tested using relevant methods, including electrophoretic mobility shift assay (EMSA), luciferase assay, and gene knockdown by lentiviral small hairpin RNA (shRNA) in lymphoblasts. RESULTS: We found one novel intronic single nucleotide variant (SNV) and three novel intergenic SNVs in the broad region of ROBO1 that were specific to the dyslexia susceptibility haplotype. Functional testing by EMSA did not support the binding of transcription factors to three of the SNVs, but one of the SNVs was bound by the LIM homeobox 2 (LHX2) protein, with increased binding affinity for the non-reference allele. Knockdown of LHX2 in lymphoblast cell lines extracted from subjects from the DYX5-linked family showed decreasing expression of ROBO1, supporting the idea that LHX2 regulates ROBO1 also in human. CONCLUSIONS: The discovered variants may explain the segregation of dyslexia in this family, but the effect appears subtle in the experimental settings. Their impact on the developing human brain remains suggestive based on the association and subtle experimental support. En ligne : http://dx.doi.org/10.1186/s11689-016-9136-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Genomic sequencing of a dyslexia susceptibility haplotype encompassing ROBO1 [texte imprimé] / Satu MASSINEN, Auteur ; Jing WANG, Auteur ; Krista LAIVUORI, Auteur ; Andrea BIEDER, Auteur ; Isabel TAPIA PAEZ, Auteur ; Hong JIAO, Auteur ; Juha KERE, Auteur . - p.4. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.4 Mots-clés : Dyslexia  Robo1  Whole genome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: The DYX5 locus for developmental dyslexia was mapped to chromosome 3 by linkage study of a large Finnish family, and later, roundabout guidance receptor 1 (ROBO1) was implicated as a candidate gene at DYX5 with suppressed expression from the segregating rare haplotype. A functional magnetoencephalographic study of several family members revealed abnormal auditory processing of interaural interaction, supporting a defect in midline crossing of auditory pathways. In the current study, we have characterized genetic variation in the broad ROBO1 gene region in the DYX5-linked family, aiming to identify variants that would increase our understanding of the altered expression of ROBO1. METHODS: We have used a whole genome sequencing strategy on a pooled sample of 19 individuals in combination with two individually sequenced genomes. The discovered genetic variants were annotated and filtered. Subsequently, the most interesting variants were functionally tested using relevant methods, including electrophoretic mobility shift assay (EMSA), luciferase assay, and gene knockdown by lentiviral small hairpin RNA (shRNA) in lymphoblasts. RESULTS: We found one novel intronic single nucleotide variant (SNV) and three novel intergenic SNVs in the broad region of ROBO1 that were specific to the dyslexia susceptibility haplotype. Functional testing by EMSA did not support the binding of transcription factors to three of the SNVs, but one of the SNVs was bound by the LIM homeobox 2 (LHX2) protein, with increased binding affinity for the non-reference allele. Knockdown of LHX2 in lymphoblast cell lines extracted from subjects from the DYX5-linked family showed decreasing expression of ROBO1, supporting the idea that LHX2 regulates ROBO1 also in human. CONCLUSIONS: The discovered variants may explain the segregation of dyslexia in this family, but the effect appears subtle in the experimental settings. Their impact on the developing human brain remains suggestive based on the association and subtle experimental support. En ligne : http://dx.doi.org/10.1186/s11689-016-9136-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

Rare variants in the outcome of social skills group training for autism / Danyang LI in Autism Research, 15-3 (March 2022)  

Public ISBD [article]  inAutism Research > 15-3 (March 2022) . - p.434-446 Titre : Rare variants in the outcome of social skills group training for autism Type de document : texte imprimé Auteurs : Danyang LI, Auteur ; Nora CHOQUE OLSSON, Auteur ; Martin BECKER, Auteur ; Abishek ARORA, Auteur ; Hong JIAO, Auteur ; Nina NORGREN, Auteur ; Ulf JONSSON, Auteur ; Sven BÖLTE, Auteur ; Kristiina TAMMIMIES, Auteur Article en page(s) : p.434-446 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Abstract Exome sequencing has been proposed as the first-tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify molecular diagnoses and genetic modifiers of intervention outcomes of social skills group training (SSGT) or standard care. We prioritized variants of clinical significance (VCS), variants of uncertain significance (VUS) and generated a pilot scheme to calculate genetic scores of rare and common variants in ASD-related gene pathways. Mixed linear models were used to test the association between the carrier status of VCS/VUS or the genetic scores with intervention outcomes measured by the social responsiveness scale. Additionally, we combined behavioral and genetic features using a machine learning (ML) model to predict the individual response. We showed a rate of 4.4% and 11.3% of VCS and VUS in the cohort, respectively. Individuals with VCS or VUS had improved significantly less after standard care than non-carriers at post-intervention (? = 9.35; p = 0.036), while no such association was observed for SSGT (? = 2.50; p = 0.65). Higher rare variant genetic scores for synaptic transmission and regulation of transcription from RNA polymerase II were separately associated with less beneficial (? = 8.30, p = 0.0044) or more beneficial (? = 6.79, p = 0.014) effects after SSGT compared with standard care at follow-up, respectively. Our ML model showed the importance of rare variants for outcome prediction. Further studies are needed to understand genetic predisposition to intervention outcomes in ASD. En ligne : https://doi.org/10.1002/aur.2666 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 [article] Rare variants in the outcome of social skills group training for autism [texte imprimé] / Danyang LI, Auteur ; Nora CHOQUE OLSSON, Auteur ; Martin BECKER, Auteur ; Abishek ARORA, Auteur ; Hong JIAO, Auteur ; Nina NORGREN, Auteur ; Ulf JONSSON, Auteur ; Sven BÖLTE, Auteur ; Kristiina TAMMIMIES, Auteur . - p.434-446. Langues : Anglais (eng) in Autism Research > 15-3 (March 2022) . - p.434-446 Index. décimale : PER Périodiques Résumé : Abstract Exome sequencing has been proposed as the first-tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify molecular diagnoses and genetic modifiers of intervention outcomes of social skills group training (SSGT) or standard care. We prioritized variants of clinical significance (VCS), variants of uncertain significance (VUS) and generated a pilot scheme to calculate genetic scores of rare and common variants in ASD-related gene pathways. Mixed linear models were used to test the association between the carrier status of VCS/VUS or the genetic scores with intervention outcomes measured by the social responsiveness scale. Additionally, we combined behavioral and genetic features using a machine learning (ML) model to predict the individual response. We showed a rate of 4.4% and 11.3% of VCS and VUS in the cohort, respectively. Individuals with VCS or VUS had improved significantly less after standard care than non-carriers at post-intervention (? = 9.35; p = 0.036), while no such association was observed for SSGT (? = 2.50; p = 0.65). Higher rare variant genetic scores for synaptic transmission and regulation of transcription from RNA polymerase II were separately associated with less beneficial (? = 8.30, p = 0.0044) or more beneficial (? = 6.79, p = 0.014) effects after SSGT compared with standard care at follow-up, respectively. Our ML model showed the importance of rare variants for outcome prediction. Further studies are needed to understand genetic predisposition to intervention outcomes in ASD. En ligne : https://doi.org/10.1002/aur.2666 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473

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