scholarly journals A framework to identify modifier genes in patients with Phelan-McDermid syndrome

2017 ◽  
Author(s):  
Anne-Claude Tabet ◽  
Thomas Rolland ◽  
Marie Ducloy ◽  
Jonathan Lévy ◽  
Julien Buratti ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Features ◽  
Clinical Symptoms ◽  
Major Gene ◽  
Autism Spectrum ◽  
Speech Impairment ◽  
Compensatory Mechanisms ◽  
Genomic Regions ◽  
Relationship Of ◽  
Degrees Of Severity

ABSTRACTPhelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability, speech impairment, and autism spectrum disorders (ASD). It results from a deletion of the 22q13 locus that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors modulating the severity of the syndrome remain largely unknown. In this study, we investigated 85 PMS patients with different 22q13 rearrangements (78 deletions, 7 duplications). We first explored their clinical features and provide evidence for frequent corpus callosum abnormalities. We then mapped candidate genomic regions at the 22q13 locus associated with risk of clinical features, and suggest a second locus associated with absence of speech. Finally, in some cases, we identified additional rearrangements at loci associated with ASD, potentially modulating the severity of the syndrome. We also report the first SHANK3 deletion transmitted to five affected daughters by a mother without intellectual disability nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

scholarly journals Widespread Genotype-Phenotype Correlations in Intellectual Disability

2017 ◽  
Author(s):  
Emily L. Casanova ◽  
Zachary Gerstner ◽  
Julia L. Sharp ◽  
Manuel F. Casanova ◽  
F. Alex Feltus
Keyword(s):  
Intellectual Disability ◽  
Clinical Features ◽  
Clinical Symptoms ◽  
Gene Interaction ◽  
Phenotypic Analysis ◽  
Human Phenotype ◽  
Genetics Research ◽  
Biochemical Mechanisms ◽  
Relevant Gene ◽  
Facial Dysmorphia

ABSTRACTBackgroundLinking genotype to phenotype is a major aim of genetics research, yet many complex conditions continue to hide their underlying biochemical mechanisms. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID.MethodsTwo hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical symptoms of complex versus simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered using via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment modules within the full ID network.ResultsPhenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to module.ConclusionsThese data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.

scholarly journals Default Mode and Fronto-Parietal Network Associations with IQ Development Across Childhood in Autism

2021 ◽  
Author(s):  
Joshua K Lee ◽  
An Chuen Billy Cho ◽  
Derek S Andrews ◽  
Sally Ozonoff ◽  
Sally J Rogers ◽  
...  
Keyword(s):  
Early Childhood ◽  
Intellectual Disability ◽  
Middle Childhood ◽  
Large Scale ◽  
Distance Matrix ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Compensatory Mechanisms ◽  
Default Mode ◽  
Low Iq

Abstract Background: Intellectual disability affects approximately one third of individuals with autism spectrum disorder (autism), yet a major unresolved question remains concerning the neurobiology that differentiates autistic individuals with and without intellectual disability. IQ is highly variable during childhood. We previously identified subgroups of autistic children with different trajectories of intellectual development from early childhood (2-3½ yeas) up to middle childhood (9-12 years): (a) Persistently-High: Individuals whose intelligence quotients (IQs) remained in the average or better range during this period, (b) Persistently-Low: Individuals whose IQs remained in the range of intellectual disability (IQ < 70) throughout development, and (c) Changers: Individuals whose IQs began in the range of intellectual disability but increased to the borderline or normal IQ range by middle childhood. In the present research, we sought to identify neurobiology that differentiates these trajectory-defined groups within our autism cohort in two brain networks with established links to intellectual functioning and its impairment in (1) the frontoparietal network (FPN), and (2) the default mode network (DMN). Methods: We conducted multivariate distance matrix regression (MDMR) and effect size analyses to examine the volumes of 22 brain regions (11 regions x 2 hemispheres) within the FPN and 24 (12 regions x 2 hemispheres) within the DMN in 48 Persistently-High (18 female), 108 Persistently-Low (32 female), and 109 Changers (39 female) using structural MRI that had been acquired at baseline, and IQ measurements from up to three time points spanning early to middle childhood (Mean Age Time 1: 3.2 years; Time 2: 5.4 years; Time 3: 11.3 years). FPN and DMN network regions of interest were defined on the basis of the large-scale networks defined in Smith et al., (2009).Results: Changers exhibited different DMN network structure from both Persistently-Low and Persistently-High trajectory groups at baseline, but the Persistently-High did not differ from the Persistently-Low group, suggesting that DMN structure may be an early predictor for change in IQ trajectory across childhood. In contrast, Persistently-High exhibited differences in the FPN from both Persistently-Low and Changers groups at baseline, suggesting a difference related more to concurrent IQ and the absence of intellectual disability. Conclusions: Within autism, DMN structure at baseline may differentiate individuals with persistently low IQ from those with more transitory low IQ that improves to the borderline range or better through early childhood, potentially indicating compensatory mechanisms which may be targeted by future interventions. The brain structure differences between these three IQ-based subgroups may be indicative of distinct neural underpinnings of autism phenotypic subtypes.

scholarly journals Rare partial trisomy and tetrasomy of 15q11-q13 associated with developmental delay and autism spectrum disorder 

2020 ◽  
Author(s):  
Yinghong Lu ◽  
Yi Liang ◽  
Sisi Ning ◽  
Guosheng Deng ◽  
Yulin Xie ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
High Resolution ◽  
Developmental Delay ◽  
Motor Development ◽  
Clinical Symptoms ◽  
Karyotype Analysis ◽  
Partial Trisomy ◽  
Autism Spectrum ◽  
Spectrum Disorder

Abstract Background: Small supernumerary marker chromosomes (sSMCs), are additional abnormal chromosomes, which can’t be detected accurately by banding cytogenetic analysis. Abnormal phenotypes were observed in about 30% of SMC carriers. Duplication of chromosome 15 and related disorders, characterized by hypotonia motor delays, autism spectrum disorder (ASD), intellectual disability, and epilepsy including infantile spasms, might be account for 50% of the total sSMCs. Case presentation: An 11-month-old infant with an sSMC fond by banding cytogenetics was referred to our clinic because of developmental retardation and autism spectrum disorder. After several months of rehabilitation treatment, the progress of motor development was obvious, but the consciousness was still far from satisfied. High-resolution karyotype analysis, multiplex ligation-dependent probe amplification and copy number variation sequencing (CNV-Seq) were conducted to confirm the identity of the sSMC. A bisatellited dicentric sSMC was observed clearly in high-resolution karyotype analysis and a 10.16-Mb duplication of 15q11.1q13.2 (3.96 copies) together with a 1.84-Mb duplication of 15q13.2q13.3 (3 copies) was showed by CNV-Seq in the proband. It suggested that the molecular cytogenetic karyotype was 47,XY,+dic(15;15)(q13.2;q13.3). Furthermore, the clinical symptoms of the proband mostly fit 15q duplication related disorders which are characterized by hypotonia motor delays, autism spectrum disorder (ASD), and intellectual disability. Conclusion: We reported for the first time using CNV-Seq to detect sSMCs and find a partial trisomy and tetrasomy of 15q11-q13 associated with developmental delay and autism spectrum disorder. Our report indicates that CNV-seq is a useful and economical way for diagnosis of dup15q and related disorders.

scholarly journals A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110583
Author(s):  
Tong Qiu ◽  
Qian Dai ◽  
Qiu Wang
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
De Novo ◽  
Clinical Symptoms ◽  
Genetic Diagnosis ◽  
Epileptic Seizures ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Severe Intellectual Disability

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing ( trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

Disorder-specific alterations of tactile sensitivity in neurodevelopmental disorders

2020 ◽  
Author(s):  
Jason He ◽  
Ericka Wodka ◽  
Mark Tommerdahl ◽  
Richard Edden ◽  
Mark Mikkelsen ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Autism Spectrum ◽  
Typically Developing ◽  
Hyperactivity Disorder ◽  
The Core ◽  
Children With Asd ◽  
Tactile Detection ◽  
Spectrum Disorders ◽  
Sensory Processes ◽  
Core Symptoms

Alterations of tactile processing have long been identified in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the extent to which these alterations are disorder-specific, rather than disorder-general, and how they relate to the core symptoms of each disorder, remains unclear. We measured and compared tactile detection, discrimination and order judgment thresholds between a large sample of children with ASD, ADHD, ASD + ADHD combined and typically developing controls. The pattern of results suggested that while difficulties with tactile detection and order judgement were more common in children with ADHD, difficulties with tactile discrimination were more common in children with ASD. Strikingly, subsequent correlation analyses found that the disorder-specific alterations suggested by the group comparisons were also exclusively related to the core symptoms of each respective disorder. These results suggest that disorder-specific alterations of lower-level sensory processes exist and are specifically related to higher-level clinical symptoms of each disorder.

scholarly journals Pediatric COVID-19 and the Factors That May Mitigate Its Clinical Course

2020 ◽  
Vol 10 (01) ◽  
pp. e137-e140
Author(s):  
Mosaad Abdel-Aziz ◽  
Nada M. Abdel-Aziz ◽  
Dina M. Abdel-Aziz ◽  
Noha Azab
Keyword(s):  
Clinical Features ◽  
Clinical Symptoms ◽  
Clinical Course ◽  
Clinical Manifestations ◽  
Gastrointestinal Symptoms ◽  
Angiotensin Converting Enzyme 2 ◽  
Compulsory Vaccination ◽  
Specific Factors ◽  
Novel Coronavirus ◽  
Radiographic Data

AbstractThe clinical manifestations of novel coronavirus disease 2019 (COVID-19) vary from mild flu-like symptoms to severe fatal pneumonia. However, children with COVID-19 may be asymptomatic or may have mild clinical symptoms. The aim of this study was to investigate clinical features of pediatric COVID-19 and to search for the factors that may mitigate the disease course. We reviewed the literature to realize the clinical features, laboratory, and radiographic data that may be diagnostic for COVID-19 among children. Also, we studied the factors that may affect the clinical course of the disease. Fever, dry cough, and fatigue are the main symptoms of pediatric COVID-19, sometimes flu-like symptoms and/or gastrointestinal symptoms may be present. Although some infected children may be asymptomatic, a recent unusual hyperinflammatory reaction with overlapping features of Kawasaki's disease and toxic shock syndrome in pediatric COVID-19 has been occasionally reported. Severe acute respiratory syndrome-coronvirus-2 (SARS-CoV-2) nucleic acid testing is the corner-stone method for the diagnosis of COVID-19. Lymphocyte count and other inflammatory markers are not essentially diagnostic; however, chest computed tomography is highly specific. Factors that may mitigate the severity of pediatric COVID-19 are home confinement with limited children activity, trained immunity caused by compulsory vaccination, the response of the angiotensin-converting enzyme 2 receptors in children is not the same as in adults, and that children are less likely to have comorbidities. As infected children may be asymptomatic or may have only mild respiratory and/or gastrointestinal symptoms that might be missed, all children for families who have a member diagnosed with COVID-19 should be investigated.

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