A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case / Claudia Ismania SAMOGY-COSTA in Journal of Neurodevelopmental Disorders, 11-1 (December 2019)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 13 p. Titre : A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case Type de document : texte imprimé Auteurs : Claudia Ismania SAMOGY-COSTA, Auteur ; Elisa VARELLA-BRANCO, Auteur ; Frederico MONFARDINI, Auteur ; Helen FERRAZ, Auteur ; Rodrigo Ambrósio FOCK, Auteur ; Ricardo Henrique Almeida BARBOSA, Auteur ; André Luiz Santos PESSOA, Auteur ; Ana Beatriz Alvarez PEREZ, Auteur ; N. LOURENCO, Auteur ; Maria VIBRANOVSKI, Auteur ; Ana KREPISCHI, Auteur ; Carla ROSENBERG, Auteur ; Maria Rita PASSOS-BUENO, Auteur Article en page(s) : 13 p. Langues : Anglais (eng) Mots-clés : 22q13.3 deletion syndrome  Autism spectrum disorder  Phelan-McDermid syndrome  Shank3 Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and mild dysmorphisms associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 haploinsufficiency has been associated with the major neurological symptoms of PMS, it cannot explain the clinical variability seen among individuals. Our goals were to characterize a Brazilian cohort of PMS individuals, explore the genotype-phenotype correlation underlying this syndrome, and describe an atypical individual with mild phenotype. METHODOLOGY: A total of 34 PMS individuals were clinically and genetically evaluated. Data were obtained by a questionnaire answered by parents, and dysmorphic features were assessed via photographic evaluation. We analyzed 22q13.3 deletions and other potentially pathogenic copy number variants (CNVs) and also performed genotype-phenotype correlation analysis to determine whether comorbidities, speech status, and ASD correlate to deletion size. Finally, a Brazilian cohort of 829 ASD individuals and another independent cohort of 2297 ID individuals was used to determine the frequency of PMS in these disorders. RESULTS: Our data showed that 21% (6/29) of the PMS individuals presented an additional rare CNV, which may contribute to clinical variability in PMS. Increased pain tolerance (80%), hypotonia (85%), and sparse eyebrows (80%) were prominent clinical features. An atypical case diagnosed with PMS at 18 years old and IQ within the normal range is here described. Among Brazilian ASD or ID individuals referred to CNV analyses, the frequency of 22q13.3 deletion was 0.6% (5/829) and 0.61% (15/2297), respectively. Finally, renal abnormalities, lymphedema, and language impairment were found to be positively associated with deletion sizes, and the minimum deletion to cause these abnormalities is here suggested. CONCLUSIONS: This is the first work describing a cohort of Brazilian individuals with PMS. Our results confirm the impact of 22q13 deletions on ASD and several comorbidities, such as hypotonia. The estimation of a minimal deletion size for developing lymphedema and renal problem can assist prediction of prognosis in PMS individuals, particularly those diagnosed in early infancy. We also identified one atypical individual carrying SHANK3 deletion, suggesting that resilience to such mutations occurs. This case expands the clinical spectrum of variability in PMS and opens perspectives to identify protective mechanisms that can minimize the severity of this condition. En ligne : https://dx.doi.org/10.1186/s11689-019-9273-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=409 [article] A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case [texte imprimé] / Claudia Ismania SAMOGY-COSTA, Auteur ; Elisa VARELLA-BRANCO, Auteur ; Frederico MONFARDINI, Auteur ; Helen FERRAZ, Auteur ; Rodrigo Ambrósio FOCK, Auteur ; Ricardo Henrique Almeida BARBOSA, Auteur ; André Luiz Santos PESSOA, Auteur ; Ana Beatriz Alvarez PEREZ, Auteur ; N. LOURENCO, Auteur ; Maria VIBRANOVSKI, Auteur ; Ana KREPISCHI, Auteur ; Carla ROSENBERG, Auteur ; Maria Rita PASSOS-BUENO, Auteur . - 13 p. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 13 p. Mots-clés : 22q13.3 deletion syndrome  Autism spectrum disorder  Phelan-McDermid syndrome  Shank3 Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and mild dysmorphisms associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 haploinsufficiency has been associated with the major neurological symptoms of PMS, it cannot explain the clinical variability seen among individuals. Our goals were to characterize a Brazilian cohort of PMS individuals, explore the genotype-phenotype correlation underlying this syndrome, and describe an atypical individual with mild phenotype. METHODOLOGY: A total of 34 PMS individuals were clinically and genetically evaluated. Data were obtained by a questionnaire answered by parents, and dysmorphic features were assessed via photographic evaluation. We analyzed 22q13.3 deletions and other potentially pathogenic copy number variants (CNVs) and also performed genotype-phenotype correlation analysis to determine whether comorbidities, speech status, and ASD correlate to deletion size. Finally, a Brazilian cohort of 829 ASD individuals and another independent cohort of 2297 ID individuals was used to determine the frequency of PMS in these disorders. RESULTS: Our data showed that 21% (6/29) of the PMS individuals presented an additional rare CNV, which may contribute to clinical variability in PMS. Increased pain tolerance (80%), hypotonia (85%), and sparse eyebrows (80%) were prominent clinical features. An atypical case diagnosed with PMS at 18 years old and IQ within the normal range is here described. Among Brazilian ASD or ID individuals referred to CNV analyses, the frequency of 22q13.3 deletion was 0.6% (5/829) and 0.61% (15/2297), respectively. Finally, renal abnormalities, lymphedema, and language impairment were found to be positively associated with deletion sizes, and the minimum deletion to cause these abnormalities is here suggested. CONCLUSIONS: This is the first work describing a cohort of Brazilian individuals with PMS. Our results confirm the impact of 22q13 deletions on ASD and several comorbidities, such as hypotonia. The estimation of a minimal deletion size for developing lymphedema and renal problem can assist prediction of prognosis in PMS individuals, particularly those diagnosed in early infancy. We also identified one atypical individual carrying SHANK3 deletion, suggesting that resilience to such mutations occurs. This case expands the clinical spectrum of variability in PMS and opens perspectives to identify protective mechanisms that can minimize the severity of this condition. En ligne : https://dx.doi.org/10.1186/s11689-019-9273-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=409

Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort / Eduarda Morgana DA SILVA MONTENEGRO in Autism Research, 13-2 (February 2020)  

Public ISBD [article]  inAutism Research > 13-2 (February 2020) . - p.199-206 Titre : Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort Type de document : texte imprimé Auteurs : Eduarda Morgana DA SILVA MONTENEGRO, Auteur ; Claudia Ismania SAMOGY-COSTA, Auteur ; Gabriele CAMPOS, Auteur ; Marilia SCLIAR, Auteur ; Tatiana Ferreira DE ALMEIDA, Auteur ; Elaine Cristina ZACHI, Auteur ; Isabela Maya Wahys SILVA, Auteur ; Ada J.S. CHAN, Auteur ; Mehdi ZARREI, Auteur ; Naila C.V. LOURENCO, Auteur ; Guilherme Lopes YAMAMOTO, Auteur ; Stephen SCHERER, Auteur ; Maria Rita PASSOS-BUENO, Auteur Article en page(s) : p.199-206 Langues : Anglais (eng) Mots-clés : Prpf8  Rmb14  Ddd  Mssng  Ssc Index. décimale : PER Périodiques Résumé : Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta-analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs: two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta-analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list): three loss-of-function pathogenic variants in CUL3, CACNA1H, and SHANK3; one missense pathogenic variant in KCNB1; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non-previous ASD genes, we prioritized PRPF8 and RBM14. Meta-analysis (n = 13,754 probands; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P-value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30: three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra-hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2020, 13: 199-206. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We believed that to study an unexplored autistic population, such as the Brazilian, could help to find novel genes for autism. In order to test this idea, with our limited budget, we compared candidate genes obtained from genomic analyses of 30 children and their parents, with those of more than 20,000 individuals from international studies. Happily, we identified a genetic cause in 23% of our patients and suggest a possible novel candidate gene for autism (PRPF8). En ligne : http://dx.doi.org/10.1002/aur.2238 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=420 [article] Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort [texte imprimé] / Eduarda Morgana DA SILVA MONTENEGRO, Auteur ; Claudia Ismania SAMOGY-COSTA, Auteur ; Gabriele CAMPOS, Auteur ; Marilia SCLIAR, Auteur ; Tatiana Ferreira DE ALMEIDA, Auteur ; Elaine Cristina ZACHI, Auteur ; Isabela Maya Wahys SILVA, Auteur ; Ada J.S. CHAN, Auteur ; Mehdi ZARREI, Auteur ; Naila C.V. LOURENCO, Auteur ; Guilherme Lopes YAMAMOTO, Auteur ; Stephen SCHERER, Auteur ; Maria Rita PASSOS-BUENO, Auteur . - p.199-206. Langues : Anglais (eng) in Autism Research > 13-2 (February 2020) . - p.199-206 Mots-clés : Prpf8  Rmb14  Ddd  Mssng  Ssc Index. décimale : PER Périodiques Résumé : Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta-analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs: two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta-analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list): three loss-of-function pathogenic variants in CUL3, CACNA1H, and SHANK3; one missense pathogenic variant in KCNB1; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non-previous ASD genes, we prioritized PRPF8 and RBM14. Meta-analysis (n = 13,754 probands; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P-value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30: three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra-hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2020, 13: 199-206. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We believed that to study an unexplored autistic population, such as the Brazilian, could help to find novel genes for autism. In order to test this idea, with our limited budget, we compared candidate genes obtained from genomic analyses of 30 children and their parents, with those of more than 20,000 individuals from international studies. Happily, we identified a genetic cause in 23% of our patients and suggest a possible novel candidate gene for autism (PRPF8). En ligne : http://dx.doi.org/10.1002/aur.2238 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=420

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