3 recherche sur le mot-clé 'Pedigree'

Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice / Stijn VAN DE SOMPELE ; Clemence LIGNEUL ; Camille CHATELAIN ; Christophe BARREA ; Jason P. LERCH ; Beatrice M. FILIPPI ; Serpil ALKAN ; Elfride DE BAERE ; Jamie JOHNSTON ; Steven J. CLAPCOTE in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 14 Titre : Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice Type de document : texte imprimé Auteurs : Stijn VAN DE SOMPELE, Auteur ; Clemence LIGNEUL, Auteur ; Camille CHATELAIN, Auteur ; Christophe BARREA, Auteur ; Jason P. LERCH, Auteur ; Beatrice M. FILIPPI, Auteur ; Serpil ALKAN, Auteur ; Elfride DE BAERE, Auteur ; Jamie JOHNSTON, Auteur ; Steven J. CLAPCOTE, Auteur Article en page(s) : 14 Langues : Anglais (eng) Mots-clés : Animals  Humans  Male  Female  Mice  Autistic Disorder/genetics  Alleles  Intellectual Disability/genetics  Pedigree  Autism Spectrum Disorder/genetics  Child  Phenotype  Behavior, Animal  Membrane Proteins/genetics  Social Behavior  Mutation  Adult  Child, Preschool  DNA-Binding Proteins  Autism spectrum disorder  Intellectual disability  Olfactory behavior  Pdzd8  Social discrimination  approved by Ghent University Ethical Committee. The affected individuals were  recruited to the study with the informed consent of their mother using a process  that adhered to the tenets of the Declaration of Helsinki. The mouse experiments  were conducted in compliance with the UK Animals (Scientific Procedures) Act 1986  under UK Home Office licences and approved by the Animal Welfare and Ethical  Review Body at the University of Leeds. Consent for publication: Written consent  for publication of case reports and images pertaining to the affected individuals  was obtained from their mother. Competing interests: The authors declare no  competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Intellectual developmental disorder with autism and dysmorphic facies (IDDADF) is a rare syndromic intellectual disability (ID) caused by homozygous disruption of PDZD8 (PDZ domain-containing protein 8), an integral endoplasmic reticulum (ER) protein. All four previously identified IDDADF cases exhibit autistic behavior, with autism spectrum disorder (ASD) diagnosed in three cases. To determine whether autistic behavior is a common outcome of PDZD8 disruption, we studied a third family with biallelic mutation of PDZD8 (family C) and further characterized PDZD8-deficient (Pdzd8(tm1b)) mice that exhibit stereotyped motor behavior relevant to ASD. METHODS: Homozygosity mapping, whole-exome sequencing, and cosegregation analysis were used to identify the PDZD8 variant responsible for IDDADF, including diagnoses of ASD, in consanguineous family C. To assess the in vivo effect of PDZD8 disruption on social responses and related phenotypes, behavioral, structural magnetic resonance imaging, and microscopy analyses were conducted on the Pdzd8(tm1b) mouse line. Metabolic activity was profiled using sealed metabolic cages. RESULTS: The discovery of a third family with IDDADF caused by biallelic disruption of PDZD8 permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism. In addition to impairments in social recognition and social odor discrimination, Pdzd8(tm1b) mice exhibit increases in locomotor activity (dark phase only) and metabolic rate (both lights-on and dark phases), and decreased plasma triglyceride in males. In the brain, Pdzd8(tm1b) mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis. LIMITATIONS: The total number of known cases of PDZD8-related IDDADF remains low. Some mouse experiments in the study did not use balanced numbers of males and females. The assessment of ER stress and mitochondrial fusion markers did not extend beyond mRNA levels. CONCLUSIONS: Our finding that the Pdzd8(tm1b) mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice. Other abnormalities exhibited by Pdzd8(tm1b) mice suggest that the range of comorbidities associated with PDZD8 deficiency may be wider than presently recognized. En ligne : https://dx.doi.org/10.1186/s13229-025-00650-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice [texte imprimé] / Stijn VAN DE SOMPELE, Auteur ; Clemence LIGNEUL, Auteur ; Camille CHATELAIN, Auteur ; Christophe BARREA, Auteur ; Jason P. LERCH, Auteur ; Beatrice M. FILIPPI, Auteur ; Serpil ALKAN, Auteur ; Elfride DE BAERE, Auteur ; Jamie JOHNSTON, Auteur ; Steven J. CLAPCOTE, Auteur . - 14. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 14 Mots-clés : Animals  Humans  Male  Female  Mice  Autistic Disorder/genetics  Alleles  Intellectual Disability/genetics  Pedigree  Autism Spectrum Disorder/genetics  Child  Phenotype  Behavior, Animal  Membrane Proteins/genetics  Social Behavior  Mutation  Adult  Child, Preschool  DNA-Binding Proteins  Autism spectrum disorder  Intellectual disability  Olfactory behavior  Pdzd8  Social discrimination  approved by Ghent University Ethical Committee. The affected individuals were  recruited to the study with the informed consent of their mother using a process  that adhered to the tenets of the Declaration of Helsinki. The mouse experiments  were conducted in compliance with the UK Animals (Scientific Procedures) Act 1986  under UK Home Office licences and approved by the Animal Welfare and Ethical  Review Body at the University of Leeds. Consent for publication: Written consent  for publication of case reports and images pertaining to the affected individuals  was obtained from their mother. Competing interests: The authors declare no  competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Intellectual developmental disorder with autism and dysmorphic facies (IDDADF) is a rare syndromic intellectual disability (ID) caused by homozygous disruption of PDZD8 (PDZ domain-containing protein 8), an integral endoplasmic reticulum (ER) protein. All four previously identified IDDADF cases exhibit autistic behavior, with autism spectrum disorder (ASD) diagnosed in three cases. To determine whether autistic behavior is a common outcome of PDZD8 disruption, we studied a third family with biallelic mutation of PDZD8 (family C) and further characterized PDZD8-deficient (Pdzd8(tm1b)) mice that exhibit stereotyped motor behavior relevant to ASD. METHODS: Homozygosity mapping, whole-exome sequencing, and cosegregation analysis were used to identify the PDZD8 variant responsible for IDDADF, including diagnoses of ASD, in consanguineous family C. To assess the in vivo effect of PDZD8 disruption on social responses and related phenotypes, behavioral, structural magnetic resonance imaging, and microscopy analyses were conducted on the Pdzd8(tm1b) mouse line. Metabolic activity was profiled using sealed metabolic cages. RESULTS: The discovery of a third family with IDDADF caused by biallelic disruption of PDZD8 permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism. In addition to impairments in social recognition and social odor discrimination, Pdzd8(tm1b) mice exhibit increases in locomotor activity (dark phase only) and metabolic rate (both lights-on and dark phases), and decreased plasma triglyceride in males. In the brain, Pdzd8(tm1b) mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis. LIMITATIONS: The total number of known cases of PDZD8-related IDDADF remains low. Some mouse experiments in the study did not use balanced numbers of males and females. The assessment of ER stress and mitochondrial fusion markers did not extend beyond mRNA levels. CONCLUSIONS: Our finding that the Pdzd8(tm1b) mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice. Other abnormalities exhibited by Pdzd8(tm1b) mice suggest that the range of comorbidities associated with PDZD8 deficiency may be wider than presently recognized. En ligne : https://dx.doi.org/10.1186/s13229-025-00650-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder / Chia-Lin YIN in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 23p. Titre : Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder Type de document : texte imprimé Auteurs : Chia-Lin YIN, Auteur ; Hsin-I CHEN, Auteur ; Ling-Hui LI, Auteur ; Yi-Ling CHIEN, Auteur ; Hsiao-Mei LIAO, Auteur ; Miao-Churn CHOU, Auteur ; Wen-Jiun CHOU, Auteur ; Wen-Che TSAI, Auteur ; Yen-Nan CHIU, Auteur ; Yu-Yu WU, Auteur ; Chen-Zen LO, Auteur ; Jer-Yuarn WU, Auteur ; Yen-Tsz CHEN, Auteur ; Susan Shur-Fen GAU, Auteur Article en page(s) : 23p. Langues : Anglais (eng) Mots-clés : Adolescent  Asian Continental Ancestry Group/genetics  Autism Spectrum Disorder/etiology/genetics  Child  China  Cohort Studies  DNA Copy Number Variations  Down-Regulation  Exons  Female  Genome-Wide Association Study  Genotype  Humans  Male  Odds Ratio  Pedigree  Phenotype  Polymorphism, Single Nucleotide  Ubiquitin-Protein Ligases/genetics  Autism spectrum disorder (ASD)  Copy number variations (CNVs)  Family study  Gene expression  Park2 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population. METHODS: To identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR). RESULTS: A total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2-4 of the PARK2 gene. CONCLUSIONS: Our finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494754. En ligne : http://dx.doi.org/10.1186/s13229-016-0087-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder [texte imprimé] / Chia-Lin YIN, Auteur ; Hsin-I CHEN, Auteur ; Ling-Hui LI, Auteur ; Yi-Ling CHIEN, Auteur ; Hsiao-Mei LIAO, Auteur ; Miao-Churn CHOU, Auteur ; Wen-Jiun CHOU, Auteur ; Wen-Che TSAI, Auteur ; Yen-Nan CHIU, Auteur ; Yu-Yu WU, Auteur ; Chen-Zen LO, Auteur ; Jer-Yuarn WU, Auteur ; Yen-Tsz CHEN, Auteur ; Susan Shur-Fen GAU, Auteur . - 23p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 23p. Mots-clés : Adolescent  Asian Continental Ancestry Group/genetics  Autism Spectrum Disorder/etiology/genetics  Child  China  Cohort Studies  DNA Copy Number Variations  Down-Regulation  Exons  Female  Genome-Wide Association Study  Genotype  Humans  Male  Odds Ratio  Pedigree  Phenotype  Polymorphism, Single Nucleotide  Ubiquitin-Protein Ligases/genetics  Autism spectrum disorder (ASD)  Copy number variations (CNVs)  Family study  Gene expression  Park2 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population. METHODS: To identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR). RESULTS: A total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2-4 of the PARK2 gene. CONCLUSIONS: Our finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494754. En ligne : http://dx.doi.org/10.1186/s13229-016-0087-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 64 p. Titre : Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Type de document : texte imprimé Article en page(s) : 64 p. Langues : Anglais (eng) Mots-clés : Adult  Autism Spectrum Disorder/*genetics  Child  Female  Humans  Male  *Models, Genetic  *Multifactorial Inheritance  *Mutation  Pedigree  Quantitative Trait Loci  *Autism spectrum disorders  *De novo mutations  *Genotype-phenotype relationship  *Multifactorial model  *Multiple hit  *Targeted sequencing  Institutional Review Board of the School of Life Sciences at Central South  University (CSU), Changsha, Hunan, China. Informed consent was obtained from the  parents or legal guardians of all study participants.Written informed consent for  publication was obtained from the parents or legal guardians.EEE is on the  scientific advisory board (SAB) of DNAnexus, Inc.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk. En ligne : https://dx.doi.org/10.1186/s13229-018-0247-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model [texte imprimé] . - 64 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 64 p. Mots-clés : Adult  Autism Spectrum Disorder/*genetics  Child  Female  Humans  Male  *Models, Genetic  *Multifactorial Inheritance  *Mutation  Pedigree  Quantitative Trait Loci  *Autism spectrum disorders  *De novo mutations  *Genotype-phenotype relationship  *Multifactorial model  *Multiple hit  *Targeted sequencing  Institutional Review Board of the School of Life Sciences at Central South  University (CSU), Changsha, Hunan, China. Informed consent was obtained from the  parents or legal guardians of all study participants.Written informed consent for  publication was obtained from the parents or legal guardians.EEE is on the  scientific advisory board (SAB) of DNAnexus, Inc.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk. En ligne : https://dx.doi.org/10.1186/s13229-018-0247-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389