Prospective and detailed behavioral phenotyping in DDX3X syndrome / L. TANG in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 36 p. Titre : Prospective and detailed behavioral phenotyping in DDX3X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : L. TANG, Auteur ; T. LEVY, Auteur ; S. GUILLORY, Auteur ; Danielle B. HALPERN, Auteur ; J. ZWEIFACH, Auteur ; I. GISERMAN-KISS, Auteur ; J. H. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; P. BELANI, Auteur ; C. LAYTON, Auteur ; B. LERMAN, Auteur ; E. FROWNER, Auteur ; Michael S. BREEN, Auteur ; S. DE RUBEIS, Auteur ; A. KOSTIC, Auteur ; A. KOLEVZON, Auteur ; Joseph D. BUXBAUM, Auteur ; P. M. SIPER, Auteur ; D. E. GRICE, Auteur Article en page(s) : 36 p. Langues : Anglais (eng) Mots-clés : Autism  DDX3X syndrome  Developmental delay  Genotype–phenotype correlation  Intellectual disability  Therapeutics, Acadia, and Sema4. PMS is the inventor of the SAND, which is licensed  by Mount Sinai to Stoelting Co. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: DDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored. METHODS: We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions. RESULTS: Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants. LIMITATIONS: Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder. CONCLUSION: This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes. En ligne : http://dx.doi.org/10.1186/s13229-021-00431-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Prospective and detailed behavioral phenotyping in DDX3X syndrome [Texte imprimé et/ou numérique] / L. TANG, Auteur ; T. LEVY, Auteur ; S. GUILLORY, Auteur ; Danielle B. HALPERN, Auteur ; J. ZWEIFACH, Auteur ; I. GISERMAN-KISS, Auteur ; J. H. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; P. BELANI, Auteur ; C. LAYTON, Auteur ; B. LERMAN, Auteur ; E. FROWNER, Auteur ; Michael S. BREEN, Auteur ; S. DE RUBEIS, Auteur ; A. KOSTIC, Auteur ; A. KOLEVZON, Auteur ; Joseph D. BUXBAUM, Auteur ; P. M. SIPER, Auteur ; D. E. GRICE, Auteur . - 36 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 36 p. Mots-clés : Autism  DDX3X syndrome  Developmental delay  Genotype–phenotype correlation  Intellectual disability  Therapeutics, Acadia, and Sema4. PMS is the inventor of the SAND, which is licensed  by Mount Sinai to Stoelting Co. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: DDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored. METHODS: We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions. RESULTS: Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants. LIMITATIONS: Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder. CONCLUSION: This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes. En ligne : http://dx.doi.org/10.1186/s13229-021-00431-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism / Michael S. BREEN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 53 p. Titre : Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism Type de document : Texte imprimé et/ou numérique Auteurs : Michael S. BREEN, Auteur ; Andrew BROWNE, Auteur ; Gabriel E. HOFFMAN, Auteur ; Sofia STATHOPOULOS, Auteur ; Kristen BRENNAND, Auteur ; Joseph D. BUXBAUM, Auteur ; Elodie DRAPEAU, Auteur Article en page(s) : 53 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Neural progenitor cells  Neurons  RNA-sequencing  Stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability, and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions. METHODS: We developed human-induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n = 7) and their unaffected siblings (n = 6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (hiPSC-NPCs; n = 39) and induced forebrain neurons (hiPSC-neurons; n = 41). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings. RESULTS: Transcriptome analyses identified 391 differentially expressed genes (DEGs) in hiPSC-NPCs and 82 DEGs in hiPSC-neurons, when comparing cells from PMS probands and unaffected siblings (FDR En ligne : http://dx.doi.org/10.1186/s13229-020-00355-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism [Texte imprimé et/ou numérique] / Michael S. BREEN, Auteur ; Andrew BROWNE, Auteur ; Gabriel E. HOFFMAN, Auteur ; Sofia STATHOPOULOS, Auteur ; Kristen BRENNAND, Auteur ; Joseph D. BUXBAUM, Auteur ; Elodie DRAPEAU, Auteur . - 53 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 53 p. Mots-clés : Autism spectrum disorder  Neural progenitor cells  Neurons  RNA-sequencing  Stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability, and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions. METHODS: We developed human-induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n = 7) and their unaffected siblings (n = 6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (hiPSC-NPCs; n = 39) and induced forebrain neurons (hiPSC-neurons; n = 41). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings. RESULTS: Transcriptome analyses identified 391 differentially expressed genes (DEGs) in hiPSC-NPCs and 82 DEGs in hiPSC-neurons, when comparing cells from PMS probands and unaffected siblings (FDR En ligne : http://dx.doi.org/10.1186/s13229-020-00355-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

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