Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder / B. MAHJANI in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 65 p. Titre : Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : B. MAHJANI, Auteur ; S. DE RUBEIS, Auteur ; C. GUSTAVSSON MAHJANI, Auteur ; M. MULHERN, Auteur ; X. XU, Auteur ; L. KLEI, Auteur ; F. K. SATTERSTROM, Auteur ; J. FU, Auteur ; Michael E. TALKOWSKI, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; D. E. GRICE, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur ; Joseph D. BUXBAUM, Auteur Article en page(s) : 65 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Copy number variant  Intellectual disability  Pages  Single nucleotide variant  Whole exome sequencing  that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00465-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder [Texte imprimé et/ou numérique] / B. MAHJANI, Auteur ; S. DE RUBEIS, Auteur ; C. GUSTAVSSON MAHJANI, Auteur ; M. MULHERN, Auteur ; X. XU, Auteur ; L. KLEI, Auteur ; F. K. SATTERSTROM, Auteur ; J. FU, Auteur ; Michael E. TALKOWSKI, Auteur ; A. REICHENBERG, Auteur ; S. SANDIN, Auteur ; C. M. HULTMAN, Auteur ; D. E. GRICE, Auteur ; K. ROEDER, Auteur ; B. DEVLIN, Auteur ; Joseph D. BUXBAUM, Auteur . - 65 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 65 p. Mots-clés : Autism spectrum disorder  Copy number variant  Intellectual disability  Pages  Single nucleotide variant  Whole exome sequencing  that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00465-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

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

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