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

The spectrum of communication abilities in children with 12 rare neurodevelopmental disorders: a qualitative study with caregivers / Christina K. ZIGLER in Journal of Child Psychology and Psychiatry, 67-5 (May 2026)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 67-5 (May 2026) . - p.740-754 Titre : The spectrum of communication abilities in children with 12 rare neurodevelopmental disorders: a qualitative study with caregivers Type de document : texte imprimé Auteurs : Christina K. ZIGLER, Auteur ; Molly MCFATRICH, Auteur ; Nicole LUCAS, Auteur ; Kate PLYLER, Auteur ; Leslie ZAPATA-LEIVA, Auteur ; Kelly GORDON, Auteur ; Harrison N. JONES, Auteur ; Li LIN, Auteur ; Jennifer KERN, Auteur ; Abigail RADAR, Auteur ; Dandan CHEN, Auteur ; Elika BERGELSON, Auteur ; Kate STILL, Auteur ; Brigette HINGER, Auteur ; Christal G. DELAGRAMMATIKAS, Auteur ; Sarah POLIQUIN, Auteur ; Brittany P. SHORT, Auteur ; Liz MARFIA-ASH, Auteur ; Kimberly STEPHENS, Auteur ; Haley O. OYLER, Auteur ; J. Michael GRAGLIA, Auteur ; Kali WORTH, Auteur ; Charlene SON RIGBY, Auteur ; James R. GOSS, Auteur ; Bo BIGELOW, Auteur ; Geraldine BLISS, Auteur ; Karen BEATTY, Auteur ; Leah SCHUST MYERS, Auteur ; Melissa THELEN, Auteur ; Nuala SUMMERFIELD, Auteur ; Terry Jo BICHELL, Auteur ; Bryce B. REEVE, Auteur Article en page(s) : p.740-754 Langues : Anglais (eng) Mots-clés : Communication  non-verbal communication  behavioural measures  qualitative methods  caregiver Index. décimale : PER Périodiques Résumé : Background Our aim was to update an existing model of communication ability for children with rare neurodevelopmental disorders (NDDs) by centring caregiver and family perspectives. This project is part of a larger initiative to improve the measurement of communication ability for these children in the context of clinical trials. Methods We conducted concept elicitation interviews with purposively selected clinical experts and caregivers of children with 12 NDDs, focusing on a broad definition of communication ability based on the Observer-Reported Communication Ability (ORCA) measure, which is inclusive of different communication modalities and covers expressive, receptive and pragmatic communication concepts. Content-based and thematic analysis was performed on the qualitative data. Results Altogether, 115 interviews were conducted with caregivers across the 12 NDDs and with 9 clinicians. Commonly mentioned concepts across NDDs included requesting an object, refusing an object, responding to familiar directions and seeking attention. There was notable heterogeneity within and across NDD groups in terms of the specific communication behaviours described for each communication concept. One common example was requesting; children used verbal speech, gestures, sign language, eye gaze, body movements and augmentative and assistive communication to ask for what they wanted. Novel communication concepts identified that were not part of the existing model were (1) feelings, emotions, and bodily sensations, (2) commenting on likes and dislikes, and (3) communicating and understanding humour. Conclusions Caregivers offered a detailed and nuanced picture of their child's day-to-day communication. There was a considerable overlap between the communication concepts discussed by caregivers in the interviews and the existing conceptual model of communication ability. Some newly identified concepts underscore the need for further adaptation of the model and subsequent validation of any clinical outcome assessment before communication ability can be confidently measured for these individuals in clinical trials. En ligne : https://doi.org/10.1111/jcpp.70063 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=586 [article] The spectrum of communication abilities in children with 12 rare neurodevelopmental disorders: a qualitative study with caregivers [texte imprimé] / Christina K. ZIGLER, Auteur ; Molly MCFATRICH, Auteur ; Nicole LUCAS, Auteur ; Kate PLYLER, Auteur ; Leslie ZAPATA-LEIVA, Auteur ; Kelly GORDON, Auteur ; Harrison N. JONES, Auteur ; Li LIN, Auteur ; Jennifer KERN, Auteur ; Abigail RADAR, Auteur ; Dandan CHEN, Auteur ; Elika BERGELSON, Auteur ; Kate STILL, Auteur ; Brigette HINGER, Auteur ; Christal G. DELAGRAMMATIKAS, Auteur ; Sarah POLIQUIN, Auteur ; Brittany P. SHORT, Auteur ; Liz MARFIA-ASH, Auteur ; Kimberly STEPHENS, Auteur ; Haley O. OYLER, Auteur ; J. Michael GRAGLIA, Auteur ; Kali WORTH, Auteur ; Charlene SON RIGBY, Auteur ; James R. GOSS, Auteur ; Bo BIGELOW, Auteur ; Geraldine BLISS, Auteur ; Karen BEATTY, Auteur ; Leah SCHUST MYERS, Auteur ; Melissa THELEN, Auteur ; Nuala SUMMERFIELD, Auteur ; Terry Jo BICHELL, Auteur ; Bryce B. REEVE, Auteur . - p.740-754. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 67-5 (May 2026) . - p.740-754 Mots-clés : Communication  non-verbal communication  behavioural measures  qualitative methods  caregiver Index. décimale : PER Périodiques Résumé : Background Our aim was to update an existing model of communication ability for children with rare neurodevelopmental disorders (NDDs) by centring caregiver and family perspectives. This project is part of a larger initiative to improve the measurement of communication ability for these children in the context of clinical trials. Methods We conducted concept elicitation interviews with purposively selected clinical experts and caregivers of children with 12 NDDs, focusing on a broad definition of communication ability based on the Observer-Reported Communication Ability (ORCA) measure, which is inclusive of different communication modalities and covers expressive, receptive and pragmatic communication concepts. Content-based and thematic analysis was performed on the qualitative data. Results Altogether, 115 interviews were conducted with caregivers across the 12 NDDs and with 9 clinicians. Commonly mentioned concepts across NDDs included requesting an object, refusing an object, responding to familiar directions and seeking attention. There was notable heterogeneity within and across NDD groups in terms of the specific communication behaviours described for each communication concept. One common example was requesting; children used verbal speech, gestures, sign language, eye gaze, body movements and augmentative and assistive communication to ask for what they wanted. Novel communication concepts identified that were not part of the existing model were (1) feelings, emotions, and bodily sensations, (2) commenting on likes and dislikes, and (3) communicating and understanding humour. Conclusions Caregivers offered a detailed and nuanced picture of their child's day-to-day communication. There was a considerable overlap between the communication concepts discussed by caregivers in the interviews and the existing conceptual model of communication ability. Some newly identified concepts underscore the need for further adaptation of the model and subsequent validation of any clinical outcome assessment before communication ability can be confidently measured for these individuals in clinical trials. En ligne : https://doi.org/10.1111/jcpp.70063 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=586

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