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Pediatric Annals Apr 2023
Topics: Child; Humans; Developmental Disabilities
PubMed: 37036774
DOI: 10.3928/19382359-20230314-01 -
Genes Jun 2021The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual... (Review)
Review
The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, and mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the gene and 118 for . These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy.
Topics: Developmental Disabilities; Epigenesis, Genetic; Extremities; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Limb Deformities, Congenital; Mutation; Phenotype; Rubinstein-Taybi Syndrome
PubMed: 34202860
DOI: 10.3390/genes12070968 -
Revista de Neurologia Jul 2021Intellectual disability is a neurodevelopmental condition characterised by cognitive deficits and functional impairments in adaptive behaviour that occur during... (Review)
Review
Intellectual disability is a neurodevelopmental condition characterised by cognitive deficits and functional impairments in adaptive behaviour that occur during development. It should be noted that this generates a variety of symptomatology, which is why it is considered by neuropsychology as an axis of analysis. In this regard, emphasis will be placed on why neuropsychological screening is necessary in this condition. Such relevance lies, on the one hand, in determining whether the child's disability is due to alterations in the nervous system or to unfavourable conditions of the environment in which he/she develops. On the other hand, neuropsychological examination provides information on which areas of the brain are responsible for one or the other disability. It also makes it possible to identify the individual particularities of the child's development, that is, his/her performance profile (strengths and weaknesses), but not necessarily to establish the diagnosis of intellectual disability and, from there, decide on intervention programmes adapted to the characteristics and needs of each case.
Topics: Child; Child, Preschool; Cultural Characteristics; Developmental Disabilities; Humans; Infant; Intellectual Disability; Neurologic Examination; Neuropsychological Tests
PubMed: 34254662
DOI: 10.33588/rn.7302.2021025 -
Molecular and Cellular Neurosciences Jun 2021The genetics of neurodevelopmental disorders (NDD) has made tremendous progress during the last few decades with the identification of more than 1,500 genes associated... (Review)
Review
The genetics of neurodevelopmental disorders (NDD) has made tremendous progress during the last few decades with the identification of more than 1,500 genes associated with conditions such as intellectual disability and autism. The functional roles of these genes are currently studied to uncover the biological mechanisms influencing the clinical outcome of the mutation carriers. To integrate the data, several databases and curated gene lists have been generated. Here, we provide an overview of the main databases focusing on the genetics of NDD, that are widely used by the medical and scientific communities, and extract a list of high confidence NDD genes (HC-NDD). This gene set can be used as a first filter for interpreting large scale omics dataset or for diagnostic purposes. Overall HC-NDD genes (N = 1,586) are expressed at very early stages of fetal brain development and enriched in several biological pathways such as chromosome organization, cell cycle, metabolism and synaptic function. Among those HC-NDD genes, 204 (12,9%) are listed in the synaptic gene ontology SynGO and are enriched in genes expressed after birth in the cerebellum and the cortex of the human brain. Finally, we point at several limitations regarding the relatively poor standardized information available, especially on the carriers of the mutations. Progress on the phenotypic characterization and genetic profiling of the carriers will be crucial to improve our knowledge on the biological mechanisms and on risk and protective factors for NDD.
Topics: Autistic Disorder; Databases, Genetic; Developmental Disabilities; Gene Regulatory Networks; Genetic Predisposition to Disease; Humans; Phenotype; Protein Interaction Maps
PubMed: 33932580
DOI: 10.1016/j.mcn.2021.103623 -
Genes Aug 2021Haploinsufficiency of has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and... (Review)
Review
Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenotype Correlation.
Haploinsufficiency of has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of is well established, clinical features of patients harboring sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3' end of the gene, confirming the genotype-phenotype correlation initially described.
Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Child; Child, Preschool; Cytoskeletal Proteins; Developmental Disabilities; Female; Genetic Association Studies; Humans; Infant; Intellectual Disability; Loss of Function Mutation; Male; Syndrome; Transcription Factors
PubMed: 34573342
DOI: 10.3390/genes12091360 -
Journal of Medical Genetics Aug 2020Developmental disorders (DDs) are early onset disorders affecting 5%-10% of children worldwide. Chromosomal microarray analysis detecting CNVs is currently recommended...
BACKGROUND
Developmental disorders (DDs) are early onset disorders affecting 5%-10% of children worldwide. Chromosomal microarray analysis detecting CNVs is currently recommended as the first-tier test for DD diagnosis. However, this analysis omits a high percentage of disease-causing single nucleotide variations (SNVs) that warrant further sequencing. Currently, next-generation sequencing can be used in clinical scenarios detecting CNVs, and the use of exome sequencing in the DD cohort ahead of the microarray test has not been evaluated.
METHODS
Clinical exome sequencing (CES) was performed on 1090 unrelated Chinese DD patients who were classified into five phenotype subgroups. CNVs and SNVs were both detected and analysed based on sequencing data.
RESULTS
An overall diagnostic rate of 41.38% was achieved with the combinational analysis of CNV and SNV. Over 12.02% of patients were diagnosed based on CNV, which was comparable with the published CMA diagnostic rate, while 0.74% were traditionally elusive cases who had dual diagnosis or apparently homozygous mutations that were clarified. The diagnostic rates among subgroups ranged from 21.82% to 50.32%. The top three recurrent cytobands with diagnostic CNVs were 15q11.2-q13.1, 22q11.21 and 7q11.23. The top three genes with diagnostic SNVs were: , and . Both the diagnostic rate and spectrums of CNVs and SNVs showed differences among the phenotype subgroups.
CONCLUSION
With a higher diagnostic rate, more comprehensive observation of variations and lower cost compared with conventional strategies, simultaneous analysis of CNVs and SNVs based on CES showed potential as a new first-tier choice to diagnose DD.
Topics: Adolescent; Child; Child, Preschool; DNA Copy Number Variations; Developmental Disabilities; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Intellectual Disability; Male; Methyl-CpG-Binding Protein 2; Microarray Analysis; Mutation; NAV1.1 Voltage-Gated Sodium Channel; NAV1.2 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide; Exome Sequencing
PubMed: 32005694
DOI: 10.1136/jmedgenet-2019-106377 -
Journal of Biosciences 2020Post-translational modification (PTM) in histone proteins is a covalent modification which mainly consists of methylation, phosphorylation, acetylation, ubiquitylation,... (Review)
Review
Post-translational modification (PTM) in histone proteins is a covalent modification which mainly consists of methylation, phosphorylation, acetylation, ubiquitylation, SUMOylation, glycosylation, and ADP-ribosylation. PTMs have fundamental roles in chromatin structure and function. Histone modifications have also been known as epigenetic markers. The PTMs that have taken place in histone proteins can affect gene expression by altering chromatin structure. Histone modifications act in varied biological processes such as transcriptional activation/inactivation, chromosome packaging, mitosis, meiosis, apoptosis, and DNA damage/repair. Defects in the PTMs pathway have been associated with the occurrence and progression of various human diseases, such as cancer, heart failure, autoimmune diseases, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. Histone modifications are reversible and used as potential targets for cancer therapy and prevention. Recent different histone PTMs have key roles in cancer cells since it has been shown that histone PTMs markers in cancers are acetylation, methylation, phosphorylation, and ubiquitylation. In this review, we have summarized the six most studied histone modifications and have examined the role of these modifications in the development of cancer.
Topics: Acetylation; Developmental Disabilities; Glycosylation; Histone Code; Histones; Humans; Nervous System Diseases; Phosphorylation; Protein Processing, Post-Translational; Ubiquitination
PubMed: 33184251
DOI: No ID Found -
Nature Nov 2023Mouse models are a critical tool for studying human diseases, particularly developmental disorders. However, conventional approaches for phenotyping may fail to detect...
Mouse models are a critical tool for studying human diseases, particularly developmental disorders. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.
Topics: Animals; Mice; Cell Nucleus; Developmental Disabilities; Embryo, Mammalian; Gain of Function Mutation; Genotype; Loss of Function Mutation; Models, Genetic; Mutation; Phenotype; Single-Cell Gene Expression Analysis; Disease Models, Animal
PubMed: 37968388
DOI: 10.1038/s41586-023-06548-w -
JAMA Pediatrics Jan 2020Therapeutic hypothermia reduces risk of death and disability in infants with moderate to severe hypoxic ischemic encephalopathy (HIE). Randomized clinical trials of...
IMPORTANCE
Therapeutic hypothermia reduces risk of death and disability in infants with moderate to severe hypoxic ischemic encephalopathy (HIE). Randomized clinical trials of therapeutic hypothermia to date have not included infants with mild HIE because of a perceived good prognosis.
OBJECTIVE
To test the hypothesis that children with mild HIE have worse neurodevelopmental outcomes than their healthy peers.
DESIGN, SETTING, AND PARTICIPANTS
Analysis of pooled data from 4 prospective cohort studies in Cork, Ireland, and Stockholm, Sweden, between January 2007 and August 2015. The dates of data analysis were September 2017 to June 2019. Follow-up was performed at age 18 to 42 months. In this multicenter cohort study, all children were born or treated at the tertiary centers of Cork University Maternity Hospital, Cork, Ireland, or Karolinska University Hospital, Stockholm, Sweden. In all, 690 children were eligible for this study.
EXPOSURES
At discharge, all children were categorized into the following 5 groups using a modified Sarnat score: healthy controls, perinatal asphyxia (PA) without HIE, mild HIE, moderate HIE, and severe HIE.
MAIN OUTCOMES AND MEASURES
Cognitive, language, and motor development were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III). The BSITD-III scores are standardized to a mean (SD) of 100 (15), with lower scores indicating risk of developmental delay.
RESULTS
Of the 690 children eligible for this study, 2-year follow-up data were available in 471 (mean [SD] age at follow-up, 25.6 [5.7] months; 54.8% male), including 152 controls, 185 children with PA without HIE, and 134 children with HIE, of whom 14 had died. Infants with mild HIE (n = 55) had lower cognitive composite scores compared with controls, with a mean (SD) of 97.6 (11.9) vs 103.6 (14.6); the crude mean difference was -6.0 (95% CI, -9.9 to -2.1), and the adjusted mean difference was -5.2 (95% CI, -9.1 to -1.3). There was no significant difference in the mean cognitive composite scores between untreated children (n = 47) with mild HIE and surviving children with moderate HIE (n = 53) treated with therapeutic hypothermia, with a crude mean difference for mild vs moderate of -2.2 (95% CI, -8.1 to 3.7).
CONCLUSIONS AND RELEVANCE
This study's findings suggest that, at age 2 years, the cognitive composite scores of children with a history of mild HIE may be lower than those of a contemporaneous control group and may not be significantly different from those of survivors of moderate HIE treated with therapeutic hypothermia.
Topics: Child Development; Child, Preschool; Developmental Disabilities; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant; Male; Prognosis; Prospective Studies
PubMed: 31710357
DOI: 10.1001/jamapediatrics.2019.4011 -
Pediatrics Feb 2021Pica, the repeated ingestion of nonfood items, can be life-threatening. Although case reports describe pica in children with autism spectrum disorder (ASD) or...
BACKGROUND AND OBJECTIVES
Pica, the repeated ingestion of nonfood items, can be life-threatening. Although case reports describe pica in children with autism spectrum disorder (ASD) or intellectual disability (ID), there has been little systematic study of pica prevalence. We assessed pica in children 30 to 68 months of age (median = 55.4 months) with and without ASD.
METHODS
Our sample from the Study to Explore Early Development, a multisite case-control study, included children with ASD ( = 1426), children with other developmental disabilities (DDs) ( = 1735), and general population-based controls (POPs) ( = 1578). We subdivided the ASD group according to whether children had ID and the DD group according to whether they had ID and/or some ASD characteristics. Standardized developmental assessments and/or questionnaires were used to define final study groups, subgroups, and pica. We examined pica prevalence in each group and compared ASD and DD groups and subgroups to the POP group using prevalence ratios adjusted for sociodemographic factors.
RESULTS
Compared with the prevalence of pica among POPs (3.5%), pica was higher in children with ASD (23.2%) and DD (8.4%), and in the following subgroups: ASD with ID (28.1%), ASD without ID (14.0%), DD with ID (9.7%), DD with ASD characteristics (12.0%), and DD with both ID and ASD characteristics (26.3%); however, pica prevalence was not elevated in children with DD with neither ID nor ASD characteristics (3.2%). Between-group differences remained after adjustment (adjusted prevalence ratio range 1.9-8.0, all <.05).
CONCLUSIONS
Pica may be common in young children with ASD, ASD characteristics, and ID. These findings inform the specialized health care needs of these children.
Topics: Adult; Autism Spectrum Disorder; Case-Control Studies; Child, Preschool; Developmental Disabilities; Female; Humans; Intellectual Disability; Male; Pica; Young Adult
PubMed: 33408069
DOI: 10.1542/peds.2020-0462