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International Journal of Molecular... Mar 2021Chromodomain helicase domain 8 () is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD). Individuals with mutations show... (Review)
Review
Chromodomain helicase domain 8 () is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD). Individuals with mutations show leading symptoms of autism, macrocephaly, and facial dysmorphisms. The molecular and cellular mechanisms underpinning the early onset and development of these symptoms are still poorly understood and prevent timely and more efficient therapies of patients. Progress in this area will require an understanding of "when, why and how cells deviate from their normal trajectories". High-throughput single-cell RNA sequencing (sc-RNAseq) directly quantifies information-bearing RNA molecules that enact each cell's biological identity. Here, we discuss recent insights from sc-RNAseq of CRISPR/Cas9-editing of during mouse neocorticogenesis and human cerebral organoids. Given that the deregulation of the balance between excitation and inhibition (E/I balance) in cortical and subcortical circuits is thought to represent a major etiopathogenetic mechanism in ASD, we focus on the question of whether, and to what degree, results from current sc-RNAseq studies support this hypothesis. Beyond that, we discuss the pros and cons of these approaches and further steps to be taken to harvest the full potential of these transformative techniques.
Topics: Animals; Autistic Disorder; Brain; DNA-Binding Proteins; Disease Susceptibility; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Mutation; Neurogenesis; Single-Cell Analysis; Transcription Factors; Transcriptome
PubMed: 33806835
DOI: 10.3390/ijms22063261 -
American Journal of Medical Genetics.... Dec 2019EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex... (Review)
Review
EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.
Topics: Brain; Humans; Malformations of Cortical Development, Group II; Microtubule-Associated Proteins; Mutation, Missense; Sequence Deletion
PubMed: 31710781
DOI: 10.1002/ajmg.c.31751 -
Molecular Genetics & Genomic Medicine Mar 2021Recent studies suggest that duplication of the 9p24.3 chromosomal locus, which includes the DOCK8 and KANK1 genes, is associated with autism spectrum disorders (ASD),...
BACKGROUND
Recent studies suggest that duplication of the 9p24.3 chromosomal locus, which includes the DOCK8 and KANK1 genes, is associated with autism spectrum disorders (ASD), intellectual disability/developmental delay (ID/DD), learning problems, language disorders, hyperactivity, and epilepsy. Correlation between this duplication and the carrier phenotype needs further discussion.
METHODS
In this study, three unrelated patients with ID/DD and ASD underwent SNP aCGH and MLPA testing. Similarities in the phenotypes of patients with 9p24.3, 15q11.2, and 16p11.2 duplications were also observed.
RESULTS
All patients with ID/DD and ASD carried the 9p24.3 duplication and showed intragenic duplication of DOCK8. Additionally, two patients had ADHD, one was hearing impaired and obese, and one had macrocephaly. Inheritance of the 9p24.3 duplication was confirmed in one patient and his sibling. In one patient KANK1 was duplicated along with DOCK8. Carriers of 9p24.3, 15q11.2, and 16p11.2 duplications showed several phenotypic similarities, with ID/DD more strongly associated with duplication of 9p24.3 than of 15q11.2 and 16p11.2.
CONCLUSION
We concluded that 9p24.3 is a likely cause of ASD and ID/DD, especially in cases of DOCK8 intragenic duplication. DOCK8 is a likely causative gene, and KANK1 aberrations a modulator, of the clinical phenotype observed. Other modulators were not excluded.
Topics: Adaptor Proteins, Signal Transducing; Child; Child, Preschool; Chromosome Disorders; Chromosome Duplication; Chromosomes, Human, Pair 9; Cytoskeletal Proteins; Developmental Disabilities; Female; Guanine Nucleotide Exchange Factors; Humans; Male; Phenotype
PubMed: 33455084
DOI: 10.1002/mgg3.1592 -
Frontiers in Global Women's Health 2023To compare the proportion of female and male fetuses classified as microcephalic (head circumference [HC] < 3rd percentile) and macrocephalic (>97th percentile) by...
OBJECTIVE
To compare the proportion of female and male fetuses classified as microcephalic (head circumference [HC] < 3rd percentile) and macrocephalic (>97th percentile) by commonly used sex-neutral growth curves.
METHODS
For fetuses evaluated at a single center, we retrospectively determined the percentile of the first fetal HC measurement between 16 and 0/7 and 21-6/7 weeks using the Hadlock, Intergrowth-21st, and NICHD growth curves. The association between sex and the likelihood of being classified as microcephalic or macrocephalic was evaluated with logistic regression.
RESULTS
Female fetuses ( = 3,006) were more likely than male fetuses ( = 3,186) to be classified as microcephalic using the Hadlock (0.4% male, 1.4% female; odds ratio female vs. male 3.7, 95% CI [1.9, 7.0], < 0.001), Intergrowth-21st (0.5% male, 1.6% female; odds ratio female vs. male 3.4, 95% CI [1.9, 6.1], < 0.001), and NICHD (0.3% male, 1.6% female; odds ratio female vs. male 5.6, 95% CI [2.7, 11.5], < 0.001) curves. Male fetuses were more likely than female fetuses to be classified as macrocephalic using the Intergrowth-21st (6.0% male, 1.5% female; odds ratio male vs. female 4.3, 95% CI [3.1, 6.0], < 0.001) and NICHD (4.7% male, 1.0% female; odds ratio male vs. female 5.1, 95% CI [3.4, 7.6], < 0.001) curves. Very low proportions of fetuses were classified as macrocephalic using the Hadlock curves (0.2% male, < 0.1% female; odds ratio male vs. female 6.6, 95% CI [0.8, 52.6]).
CONCLUSION
Female fetuses were more likely to be classified as microcephalic, and male fetuses were more likely to be classified as macrocephalic. Sex-specific fetal head circumference growth curves could improve interpretation of fetal head circumference measurements, potentially decreasing over- and under-diagnosis of microcephaly and macrocephaly based on sex, therefore improving guidance for clinical decisions. Additionally, the overall prevalence of atypical head size varied using three growth curves, with the NICHD and Intergrowth-21st curves fitting our population better than the Hadlock curves. The choice of fetal head circumference growth curves may substantially impact clinical care.
PubMed: 36911049
DOI: 10.3389/fgwh.2023.1080175 -
Journal of Clinical Medicine Jan 2021Chromodomain Helicase DNA-binding 8 () is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental... (Review)
Review
Chromodomain Helicase DNA-binding 8 () is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex-specific effects of mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including 'humanized' mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans.
PubMed: 33477995
DOI: 10.3390/jcm10020366 -
Translational Psychiatry Oct 2022CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies...
CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies have shown that intellectual developmental disorder with autism and macrocephaly (IDDAM), the syndrome caused by pathogenic variants in CHD8, consists of a broad range of phenotypic abnormalities. We collected and reviewed 106 individuals with IDDAM, including 36 individuals not previously published, thus enabling thorough genotype-phenotype analyses, involving the CHD8 mutation spectrum, characterization of the CHD8 DNA methylation episignature, and the systematic analysis of phenotypes collected in Human Phenotype Ontology (HPO). We identified 29 unique nonsense, 25 frameshift, 24 missense, and 12 splice site variants. Furthermore, two unique inframe deletions, one larger deletion (exons 26-28), and one translocation were observed. Methylation analysis was performed for 13 patients, 11 of which showed the previously established episignature for IDDAM (85%) associated with CHD8 haploinsufficiency, one analysis was inconclusive, and one showing a possible gain-of-function signature instead of the expected haploinsufficiency signature was observed. Consistent with previous studies, phenotypical abnormalities affected multiple organ systems. Many neurological abnormalities, like intellectual disability (68%) and hypotonia (29%) were observed, as well as a wide variety of behavioural abnormalities (88%). Most frequently observed behavioural problems included autism spectrum disorder (76%), short attention span (32%), abnormal social behaviour (31%), sleep disturbance (29%) and impaired social interactions (28%). Furthermore, abnormalities in the digestive (53%), musculoskeletal (79%) and genitourinary systems (18%) were noted. Although no significant difference in severity was observed between males and females, individuals with a missense variant were less severely affected. Our study provides an extensive review of all phenotypic abnormalities in patients with IDDAM and provides clinical recommendations, which will be of significant value to individuals with a pathogenic variant in CHD8, their families, and clinicians as it gives a more refined insight into the clinical and molecular spectrum of IDDAM, which is essential for accurate care and counselling.
Topics: Autism Spectrum Disorder; Autistic Disorder; DNA-Binding Proteins; Female; Genetic Association Studies; Humans; Intellectual Disability; Male; Megalencephaly; Phenotype; Transcription Factors
PubMed: 36182950
DOI: 10.1038/s41398-022-02189-1 -
Frontiers in Neuroscience 2023Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and... (Review)
Review
Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.
PubMed: 36845425
DOI: 10.3389/fnins.2023.989109 -
The Journal of International Advanced... Mar 2022Sotos syndrome is a rare genetic disorder characterized by neurodevelopmental delay and excessive childhood growth including macrocephaly. In this study, we present our...
BACKGROUND
Sotos syndrome is a rare genetic disorder characterized by neurodevelopmental delay and excessive childhood growth including macrocephaly. In this study, we present our experience of children with Sotos syndrome and cholesteatoma.
METHODS
Retrospective case note review and cross-referencing with hospital picture archive and communication systems or cases identified from a prospective database of consecutive cholesteatoma surgeries.
RESULTS
A total of 400 children underwent surgery for acquired cholesteatoma and 5 (1%) had Sotos syndrome (1 bilaterally). In comparison, 42(11%) had cleft palate which is around 10 times more common than Sotos syndrome, 5 (1%) had Down syndrome, and 3 (1%) had Turner syndrome. The median age at primary surgery was 8 years old (3.5-10.9 years), 124 children with Sotos syndrome were identified in picture archive and communication systems (4% with cholesteatoma) of which temporal bone imaging was available in 86 (70%) at the median age of 9 years (0-17.2), and 33/86 (38%) had normal ears bilaterally on all imaging. Changes consistent with fluid or inflammation were present in 9/30 (30%) computed tomography and 24/72 (33%) magnetic resonance imaging scans. Development of mastoid pneumatization was impaired in 20/30 (67%) computed tomography and 8/72 (11%) magnetic resonance imaging scans. At 5 years, children with Sotos syndrome (33%) had greater recidivism than those with cleft palate (15%) (Kaplan-Meier log-rank analysis, P=.001) CONCLUSION: Children with Sotos syndrome appear to be at increased risk of developing acquired cholesteatoma. Impaired temporal bone pneumatization is a common incidental finding in Sotos syndrome in keeping with this risk. Further study of this previously unreported association may improve the understanding of pathogenetic mechanisms in cholesteatoma.
Topics: Child; Cholesteatoma, Middle Ear; Cleft Palate; Humans; Mastoid; Retrospective Studies; Sotos Syndrome
PubMed: 35418362
DOI: 10.5152/iao.2022.21309 -
Cold Spring Harbor Molecular Case... Jun 2023PPP2 syndrome type R5D, or Jordan's syndrome, is a neurodevelopmental disorder caused by pathogenic missense variants in , a β-subunit of the Protein Phosphatase 2A...
PPP2 syndrome type R5D, or Jordan's syndrome, is a neurodevelopmental disorder caused by pathogenic missense variants in , a β-subunit of the Protein Phosphatase 2A (PP2A). The condition is characterized by global developmental delays, seizures, macrocephaly, ophthalmological abnormalities, hypotonia, attention disorder, social and sensory challenges often associated with autism, disordered sleep, and feeding difficulties. Among affected individuals, there is a broad spectrum of severity, and each person only has a subset of all associated symptoms. Some, but not all, of the clinical variability is due to differences in the genotype. These suggested clinical care guidelines for the evaluation and treatment of individuals with PPP2 syndrome type R5D are based on data from 100 individuals reported in the literature and from an ongoing natural history study. As more data are available, particularly for adults and regarding treatment response, we anticipate that revisions to these guidelines will be made.
Topics: Adult; Humans; Intellectual Disability; Jordan; Neurodevelopmental Disorders; Autistic Disorder; Syndrome; Reference Standards; Protein Phosphatase 2
PubMed: 37339871
DOI: 10.1101/mcs.a006285 -
Current Opinion in Neurobiology Apr 2023How to generate a brain of correct size and with appropriate cell-type diversity during development is a major question in Neuroscience. In the developing neocortex,... (Review)
Review
How to generate a brain of correct size and with appropriate cell-type diversity during development is a major question in Neuroscience. In the developing neocortex, radial glial progenitor (RGP) cells are the main neural stem cells that produce cortical excitatory projection neurons, glial cells, and establish the prospective postnatal stem cell niche in the lateral ventricles. RGPs follow a tightly orchestrated developmental program that when disrupted can result in severe cortical malformations such as microcephaly and megalencephaly. The precise cellular and molecular mechanisms instructing faithful RGP lineage progression are however not well understood. This review will summarize recent conceptual advances that contribute to our understanding of the general principles of RGP lineage progression.
Topics: Neurons; Prospective Studies; Neurogenesis; Neural Stem Cells; Cerebral Cortex; Neocortex; Cell Lineage
PubMed: 36842274
DOI: 10.1016/j.conb.2023.102695