Phenome-wide profiling identifies genotype-phenotype associations in Phelan-McDermid syndrome using family-sourced data from an international registry / Rui YIN in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 40p. Titre : Phenome-wide profiling identifies genotype-phenotype associations in Phelan-McDermid syndrome using family-sourced data from an international registry Type de document : texte imprimé Auteurs : Rui YIN, Auteur ; Maxime WACK, Auteur ; Claire HASSEN-KHODJA, Auteur ; Michael T. MCDUFFIE, Auteur ; Geraldine BLISS, Auteur ; Elizabeth J. HORN, Auteur ; Cartik KOTHARI, Auteur ; Brittany MCLARNEY, Auteur ; Rebecca DAVIS, Auteur ; Kristen HANSON, Auteur ; Megan O'BOYLE, Auteur ; Catalina BETANCUR, Auteur ; Paul AVILLACH, Auteur Article en page(s) : 40p. Langues : Anglais (eng) Mots-clés : Humans  Registries  Chromosome Deletion  Chromosomes, Human, Pair 22/genetics  Male  Chromosome Disorders/genetics  Female  Phenotype  Genetic Association Studies  Child  Child, Preschool  Nerve Tissue Proteins/genetics  Adolescent  Adult  Young Adult  Family  Infant  Shank3  22q13.3 deletion  Phelan-McDermid syndrome  Phenome-wide association study  competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by 22q13 deletions that include the SHANK3 gene or pathogenic sequence variants in SHANK3. It is characterized by global developmental delay, intellectual disability, speech impairment, autism spectrum disorder, and hypotonia; other variable features include epilepsy, brain and renal malformations, and mild dysmorphic features. Here, we conducted genotype-phenotype correlation analyses using the PMS International Registry, a family-driven registry that compiles clinical data in the form of family-reported outcomes and family-sourced genetic test results. METHODS: Data from the registry were harmonized and integrated into the i2b2/tranSMART clinical and genomics data warehouse. We gathered information from 401 individuals with 22q13 deletions including SHANK3 (n = 350, ranging in size from 10 kb to 9.1 Mb) or pathogenic or likely pathogenic SHANK3 sequence variants (n = 51), and used regression models with deletion size as a potential predictor of clinical outcomes for 328 phenotypes. RESULTS: Our results showed that increased deletion size was significantly associated with delay in gross and fine motor acquisitions, a spectrum of conditions related to poor muscle tone, renal malformations, mild dysmorphic features (e.g., large fleshy hands, sacral dimple, dysplastic toenails, supernumerary teeth), lymphedema, congenital heart defects, and more frequent neuroimaging abnormalities and infections. These findings indicate that genes upstream of SHANK3 also contribute to some of the manifestations of PMS in individuals with larger deletions. We also showed that self-help skills, verbal ability and a range of psychiatric diagnoses (e.g., autism, ADHD, anxiety disorder) were more common among individuals with smaller deletions and SHANK3 variants. LIMITATIONS: Some participants were tested with targeted 22q microarrays rather than genome-wide arrays, and karyotypes were unavailable in many cases, thus precluding the analysis of the effect of other copy number variants or chromosomal rearrangements on the phenotype. CONCLUSIONS: This is the largest reported case series of individuals with PMS. Overall, we demonstrate the feasibility of using data from a family-sourced registry to conduct genotype-phenotype analyses in rare genetic disorders. We replicate and strengthen previous findings, and reveal novel associations between larger 22q13 deletions and congenital heart defects, neuroimaging abnormalities and recurrent infections. En ligne : https://dx.doi.org/10.1186/s13229-024-00619-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Phenome-wide profiling identifies genotype-phenotype associations in Phelan-McDermid syndrome using family-sourced data from an international registry [texte imprimé] / Rui YIN, Auteur ; Maxime WACK, Auteur ; Claire HASSEN-KHODJA, Auteur ; Michael T. MCDUFFIE, Auteur ; Geraldine BLISS, Auteur ; Elizabeth J. HORN, Auteur ; Cartik KOTHARI, Auteur ; Brittany MCLARNEY, Auteur ; Rebecca DAVIS, Auteur ; Kristen HANSON, Auteur ; Megan O'BOYLE, Auteur ; Catalina BETANCUR, Auteur ; Paul AVILLACH, Auteur . - 40p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 40p. Mots-clés : Humans  Registries  Chromosome Deletion  Chromosomes, Human, Pair 22/genetics  Male  Chromosome Disorders/genetics  Female  Phenotype  Genetic Association Studies  Child  Child, Preschool  Nerve Tissue Proteins/genetics  Adolescent  Adult  Young Adult  Family  Infant  Shank3  22q13.3 deletion  Phelan-McDermid syndrome  Phenome-wide association study  competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by 22q13 deletions that include the SHANK3 gene or pathogenic sequence variants in SHANK3. It is characterized by global developmental delay, intellectual disability, speech impairment, autism spectrum disorder, and hypotonia; other variable features include epilepsy, brain and renal malformations, and mild dysmorphic features. Here, we conducted genotype-phenotype correlation analyses using the PMS International Registry, a family-driven registry that compiles clinical data in the form of family-reported outcomes and family-sourced genetic test results. METHODS: Data from the registry were harmonized and integrated into the i2b2/tranSMART clinical and genomics data warehouse. We gathered information from 401 individuals with 22q13 deletions including SHANK3 (n = 350, ranging in size from 10 kb to 9.1 Mb) or pathogenic or likely pathogenic SHANK3 sequence variants (n = 51), and used regression models with deletion size as a potential predictor of clinical outcomes for 328 phenotypes. RESULTS: Our results showed that increased deletion size was significantly associated with delay in gross and fine motor acquisitions, a spectrum of conditions related to poor muscle tone, renal malformations, mild dysmorphic features (e.g., large fleshy hands, sacral dimple, dysplastic toenails, supernumerary teeth), lymphedema, congenital heart defects, and more frequent neuroimaging abnormalities and infections. These findings indicate that genes upstream of SHANK3 also contribute to some of the manifestations of PMS in individuals with larger deletions. We also showed that self-help skills, verbal ability and a range of psychiatric diagnoses (e.g., autism, ADHD, anxiety disorder) were more common among individuals with smaller deletions and SHANK3 variants. LIMITATIONS: Some participants were tested with targeted 22q microarrays rather than genome-wide arrays, and karyotypes were unavailable in many cases, thus precluding the analysis of the effect of other copy number variants or chromosomal rearrangements on the phenotype. CONCLUSIONS: This is the largest reported case series of individuals with PMS. Overall, we demonstrate the feasibility of using data from a family-sourced registry to conduct genotype-phenotype analyses in rare genetic disorders. We replicate and strengthen previous findings, and reveal novel associations between larger 22q13 deletions and congenital heart defects, neuroimaging abnormalities and recurrent infections. En ligne : https://dx.doi.org/10.1186/s13229-024-00619-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Psychiatric illness and regression in individuals with Phelan-McDermid syndrome / Teresa M. KOHLENBERG in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Psychiatric illness and regression in individuals with Phelan-McDermid syndrome Type de document : texte imprimé Auteurs : Teresa M. KOHLENBERG, Auteur ; M. Pilar TRELLES, Auteur ; Brittany MCLARNEY, Auteur ; Catalina BETANCUR, Auteur ; Audrey THURM, Auteur ; Alexander KOLEVZON, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Bipolar Disorder/epidemiology  Catatonia/epidemiology  Chromosome Deletion  Chromosome Disorders/psychology  Chromosomes, Human, Pair 22  Female  Humans  Male  Mental Disorders/epidemiology  Middle Aged  Phenotype  Regression, Psychology  Young Adult  Bipolar disorder  Catatonia  Depression  Mania  Phelan-McDermid syndrome  Psychosis  Regression  SHANK3  Takeda, 5 AM Ventures, sema4, and LabCorp. The other authors declare that they  have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic condition characterized by intellectual disability, speech and language deficits, hypotonia, autism spectrum disorder, and epilepsy. PMS is caused by 22q13.33 deletions or mutations affecting SHANK3, which codes for a critical scaffolding protein in excitatory synapses. SHANK3 variants are also known to be associated with an increased risk for regression, as well as for psychiatric disorders, including bipolar disorder and catatonia. This study aimed to further describe these phenomena in PMS and to explore any relationship between psychiatric illness and regression after early childhood. METHODS: Thirty-eight people with PMS were recruited to this study through the Phelan-McDermid Syndrome Foundation based on caregiver report of distinct development of psychiatric symptoms. Caregivers completed a clinician-administered semi-structured interview focused on eliciting psychiatric symptomatology. Data from the PMS International Registry were used to confirm genetic diagnoses of participants and to provide a larger sample for comparison. RESULTS: The mean age of the 38 participants was 24.7 years (range = 13 to 50; SD = 10.06). Females (31 of 38 cases; 82%) and sequence variants (15 of 38 cases; 39%) were over-represented in this sample, compared to base rates in the PMS International Registry. Onset of psychiatric symptoms occurred at a mean age of 15.4 years (range = 7 to 32), with presentations marked by prominent disturbances of mood. Enduring substantial loss of functional skills after onset of psychiatric changes was seen in 25 cases (66%). Symptomst indicative of catatonia occurred in 20 cases (53%). Triggers included infections, changes in hormonal status, and stressful life events. CONCLUSIONS: This study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in adolescence or early adulthood, including bipolar disorder, catatonia, and lasting regression of skills. These findings should increase the awareness of these phenotypes and lead to earlier diagnosis and the implementation of appropriate interventions. Our findings also highlight the importance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric disorders and regression among larger unbiased samples of individuals with PMS. En ligne : https://dx.doi.org/10.1186/s11689-020-9309-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Psychiatric illness and regression in individuals with Phelan-McDermid syndrome [texte imprimé] / Teresa M. KOHLENBERG, Auteur ; M. Pilar TRELLES, Auteur ; Brittany MCLARNEY, Auteur ; Catalina BETANCUR, Auteur ; Audrey THURM, Auteur ; Alexander KOLEVZON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Adolescent  Adult  Bipolar Disorder/epidemiology  Catatonia/epidemiology  Chromosome Deletion  Chromosome Disorders/psychology  Chromosomes, Human, Pair 22  Female  Humans  Male  Mental Disorders/epidemiology  Middle Aged  Phenotype  Regression, Psychology  Young Adult  Bipolar disorder  Catatonia  Depression  Mania  Phelan-McDermid syndrome  Psychosis  Regression  SHANK3  Takeda, 5 AM Ventures, sema4, and LabCorp. The other authors declare that they  have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic condition characterized by intellectual disability, speech and language deficits, hypotonia, autism spectrum disorder, and epilepsy. PMS is caused by 22q13.33 deletions or mutations affecting SHANK3, which codes for a critical scaffolding protein in excitatory synapses. SHANK3 variants are also known to be associated with an increased risk for regression, as well as for psychiatric disorders, including bipolar disorder and catatonia. This study aimed to further describe these phenomena in PMS and to explore any relationship between psychiatric illness and regression after early childhood. METHODS: Thirty-eight people with PMS were recruited to this study through the Phelan-McDermid Syndrome Foundation based on caregiver report of distinct development of psychiatric symptoms. Caregivers completed a clinician-administered semi-structured interview focused on eliciting psychiatric symptomatology. Data from the PMS International Registry were used to confirm genetic diagnoses of participants and to provide a larger sample for comparison. RESULTS: The mean age of the 38 participants was 24.7 years (range = 13 to 50; SD = 10.06). Females (31 of 38 cases; 82%) and sequence variants (15 of 38 cases; 39%) were over-represented in this sample, compared to base rates in the PMS International Registry. Onset of psychiatric symptoms occurred at a mean age of 15.4 years (range = 7 to 32), with presentations marked by prominent disturbances of mood. Enduring substantial loss of functional skills after onset of psychiatric changes was seen in 25 cases (66%). Symptomst indicative of catatonia occurred in 20 cases (53%). Triggers included infections, changes in hormonal status, and stressful life events. CONCLUSIONS: This study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in adolescence or early adulthood, including bipolar disorder, catatonia, and lasting regression of skills. These findings should increase the awareness of these phenotypes and lead to earlier diagnosis and the implementation of appropriate interventions. Our findings also highlight the importance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric disorders and regression among larger unbiased samples of individuals with PMS. En ligne : https://dx.doi.org/10.1186/s11689-020-9309-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

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