scholarly journals Gene discoveries in autism are biased towards comorbidity with intellectual disability

2020 ◽  
Vol 57 (9) ◽  
pp. 647-652
Author(s):  
Matthew Jensen ◽  
Corrine Smolen ◽  
Santhosh Girirajan
Keyword(s):  
Intellectual Disability ◽  
Genetic Factors ◽  
De Novo ◽  
High Functioning Autism ◽  
Copy Number Variants ◽  
Social Responsiveness ◽  
High Functioning ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Normal Cognitive Function

BackgroundAutism typically presents with highly heterogeneous features, including frequent comorbidity with intellectual disability (ID). The overlap between these phenotypes has confounded the diagnosis and discovery of genetic factors associated with autism. We analysed pathogenic de novo genetic variants in individuals with autism who had either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity.MethodsWe analysed 2290 individuals from the Simons Simplex Collection for de novo likely gene-disruptive (LGD) variants and copy-number variants (CNVs), and determined their relevance towards IQ and Social Responsiveness Scale (SRS) measures.ResultsIndividuals who carried de novo variants in a set of 173 autism-associated genes showed an average 12.8-point decrease in IQ scores (p=5.49×10−6) and 2.8-point increase in SRS scores (p=0.013) compared with individuals without such variants. Furthermore, individuals with high-functioning autism (IQ >100) had lower frequencies of de novo LGD variants (42 of 397 vs 86 of 562, p=0.021) and CNVs (9 of 397 vs 24 of 562, p=0.065) compared with individuals who manifested both autism and ID (IQ <70). Pathogenic variants disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID, while de novo variants observed in individuals with high-functioning autism disrupted genes with little functional relevance towards neurodevelopment.ConclusionsPathogenic de novo variants disrupting autism-associated genes contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.

scholarly journals Gene discoveries in autism are biased towards comorbidity with intellectual disability

2019 ◽  
Author(s):  
Matthew Jensen ◽  
Corrine Smolen ◽  
Santhosh Girirajan
Keyword(s):  
Intellectual Disability ◽  
Genetic Factors ◽  
De Novo ◽  
High Functioning Autism ◽  
Case Reports ◽  
Expression Patterns ◽  
High Functioning ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Normal Cognitive Function

AbstractAutism typically presents with a highly heterogeneous set of features, including frequent comorbidity with intellectual disability (ID). The overlap between these two phenotypes has confounded the accurate diagnosis and discovery of genetic factors associated with autism. We analyzed genetic variants in 2,290 individuals with autism from the Simons Simplex Collection (SSC) who have either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity. We found that individuals who carried variants in a set of 173 reported autism-associated genes showed decreased IQ (p=5.49×10−6) and increased autism severity (p=0.013) compared with individuals without such variants. A subset of autism-associated genes also showed strong evidence for ID comorbidity in published case reports. We also found that individuals with high-functioning autism (IQ>100) had lower frequencies of CNVs (p=0.065) and LGD variants (p=0.021) compared with individuals who manifested both autism and ID (IQ<70). These data indicated that de novo LGD variants conferred a 1.53-fold higher risk (p=0.035) towards comorbid ID, while LGD mutations specifically disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID. Furthermore, de novo LGD variants in individuals with high-functioning autism were more likely to disrupt genes with little functional relevance towards neurodevelopment, as demonstrated by evidence from pathogenicity metrics, expression patterns in the developing brain, and mouse model phenotypes. Overall, our data suggest that de novo pathogenic variants disrupting genes associated with autism contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.

scholarly journals Migration and autism spectrum disorder: population-based study

2012 ◽  
Vol 201 (2) ◽  
pp. 109-115 ◽  
Author(s):  
Cecilia Magnusson ◽  
Dheeraj Rai ◽  
Anna Goodman ◽  
Michael Lundberg ◽  
Selma Idring ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
High Functioning Autism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
High Functioning ◽  
Increased Risk ◽  
Timing Of Migration ◽  
Low Functioning ◽  
Migrant Parents

BackgroundMigration has been implicated as a risk factor for autism, but evidence is limited and inconsistent.AimsTo investigate the relationship between parental migration status and risk of autism spectrum disorder, taking into consideration the importance of region of origin, timing of migration and possible discrepancies in associations between autism subtypes.MethodRecord-linkage study within the total child population of Stockholm County between 2001 and 2007. Individuals with high- and low-functioning autism were defined as having autism spectrum disorder with and without comorbid intellectual disability, and ascertained via health and habilitation service registers.ResultsIn total, 4952 individuals with autism spectrum disorder were identified, comprising 2855 children with high-functioning autism and 2097 children with low-functioning autism. Children of migrant parents were at increased risk of low-functioning autism (odds ratio (OR) = 1.5, 95% CI 1.3–1.7); this risk was highest when parents migrated from regions with a low human development index, and peaked when migration occurred around pregnancy (OR = 2.3, 95% CI 1.7–3.0). A decreased risk of high-functioning autism was observed in children of migrant parents, regardless of area of origin or timing of migration. Parental age, income or obstetric complications did not fully explain any of these associations.ConclusionsEnvironmental factors associated with migration may contribute to the development of autism presenting with comorbid intellectual disability, especially when actingin utero.High- and low-functioning autism may have partly different aetiologies, and should be studied separately.

scholarly journals Truncating Variant Burden in High Functioning Autism and Pleiotropic Effects of LRP1 Across Psychiatric Phenotypes

2018 ◽  
Author(s):  
Bàrbara Torrico ◽  
Alex D Shaw ◽  
Roberto Mosca ◽  
Norma Vivó-Luque ◽  
Amaia Hervás ◽  
...  
Keyword(s):  
Rare Variants ◽  
De Novo ◽  
High Functioning Autism ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Pleiotropic Effects ◽  
Psychiatric Diseases ◽  
High Functioning ◽  
Pathogenic Variants ◽  
Functional Consequences

AbstractPrevious research has implicated de novo (DN) and inherited truncating mutations in autism spectrum disorder (ASD). We aim to investigate whether the load of inherited truncating mutations contribute similarly to high functioning autism (HFA), and to characterise genes harbouring DN variants in HFA.We performed whole-exome sequencing (WES) in 20 HFA families (average IQ = 100). No difference was observed in the number of transmitted versus non-transmitted truncating alleles to HFA (117 vs 130, P = 0.32). Transmitted truncating and DN variants in HFA were not enriched in GO or KEGG categories, nor autism-related gene sets. However, in a HFA patient we identified a DN variant in a canonical splice site of LRP1, a post-synaptic density gene that is a target for the FMRP. This DN leads to in-frame skipping of exon-29, removing 2 of 6 blades of the β-propeller domain-4 of LRP1, with putative functional consequences. Results using large datasets implicate LRP1 across psychiatric diseases: i) DN are associated with ASD (P = 0.039) and schizophrenia (P = 0.008) from combined sequencing projects; ii) Common variants using Psychiatric Genomics Consortium GWAS datasets show gene-based association in schizophrenia (P = 6.6E-07) and across six psychiatric diseases (meta-analysis P = 8.1E-05); and iii) burden of ultra-rare pathogenic variants is higher in ASD (P = 1.2E-05), using WES from 6,135 schizophrenia patients, 1,778 ASD patients and 6,245 controls. Previous and current studies suggest an impact of truncating mutations restricted to severe ASD phenotypes associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.

scholarly journals A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Giada Moresco ◽  
Jole Costanza ◽  
Carlo Santaniello ◽  
Ornella Rondinone ◽  
Federico Grilli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Signs ◽  
Missense Variant ◽  
Psychomotor Development ◽  
Helicase Domain ◽  
Protein Activity ◽  
Mrna Metabolism ◽  
Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

Social impairment in children with epilepsy assessed by the social responsiveness scale

2021 ◽  
pp. 135910452110331
Author(s):  
Samah K Aburahma ◽  
Hanan Hammouri ◽  
Ethar Hazaimeh ◽  
Omar Jbarah ◽  
Ahmad Nassar ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Social Responsiveness Scale ◽  
Social Impairment ◽  
Control Group ◽  
Social Responsiveness ◽  
Healthy Children ◽  
Normal Children ◽  
Social Impairments ◽  
Increased Risk ◽  
The Social

Children with epilepsy are at risk for impaired social cognition and autism. We aimed at evaluating the utility of the social responsiveness scale (SRS) for assessment of social impairment in these children. Prospective study; the SRS was applied to a group of children with epilepsy and a healthy control group. Intellectual disability in the epilepsy group was assessed utilizing adapted versions of the Wechsler Intelligence and adaptive behavior scales. One hundred and one children with epilepsy and 92 healthy children were included. The majority of children in both groups had normal SRS scores. Significant differences were identified in children with high total scores indicating significant deficiencies in reciprocal social behavior; high scores were found in 16% of children with epilepsy versus 7% of normal children, p < .05, particularly involving social communication, p < .05. Intellectual disability was identified in 42% of children with epilepsy, particularly processing speed index, p < .001. Intellectual disability had a significant effect on total scores, p = .016. Children with epilepsy have increased risk of social impairments. Social impairments are more likely in the presence of intellectual disability. The SRS is a quick identification tool that can be employed in the outpatient setting.

Genomic Syndromes in Schizophrenia

2013 ◽  
pp. 247-255
Author(s):  
George Kirov ◽  
Michael C. O’Donovan ◽  
Michael J. Owen
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Individual Risk ◽  
Genomic Deletions ◽  
Pathogenic Cnvs ◽  
Cognition And Learning

Several submicroscopic genomic deletions and duplications known as copy number variants (CNVs) have been reported to increase susceptibility to schizophrenia. Those for which the evidence is particularly strong include deletions at chromosomal segments 1q21.1, 3q29, 15q11.2, 15q13.3, 17q12 and 22q11.2, duplications at 15q11.2-q13.1, 16p13.1, and 16p11.2, and deletions atthe gene NRXN1. The effect of each on individual risk is relatively large, but it does not appear that any of them is alone sufficient to cause disorder in carriers. These CNVs often arise as new mutations(de novo). Analyses of genes enriched among schizophrenia implicated CNVs highlight the involvement in the disorder of post-synaptic processes relevant to glutamatergicsignalling, cognition and learning. CNVs that contribute to schizophrenia risk also contribute to other neurodevelopmental disorders, including intellectual disability, developmental delay and autism. As a result of selection, all known pathogenic CNVs are rare, and none makes a sizeable contribution to overall population risk of schizophrenia, although the study of these mutations is nevertheless providing important insights into the origins of the disorder.

scholarly journals Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Diana C. Dima ◽  
Rachael Adams ◽  
Stefanie C. Linden ◽  
Alister Baird ◽  
Jacqueline Smith ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Copy Number ◽  
Genetic Factors ◽  
Copy Number Variants ◽  
Neural Correlates ◽  
Common Mechanism ◽  
Node Centrality ◽  
Neural Integration ◽  
Increased Risk ◽  
Theory Framework

Abstract Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal, and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.

scholarly journals Interests in high-functioning autism are more intense, interfering, and idiosyncratic than those in neurotypical development

2013 ◽  
Vol 25 (3) ◽  
pp. 643-652 ◽  
Author(s):  
Laura Gutermuth Anthony ◽  
Lauren Kenworthy ◽  
Benjamin E. Yerys ◽  
Kathryn F. Jankowski ◽  
Joette D. James ◽  
...  
Keyword(s):  
High Functioning Autism ◽  
Repetitive Behavior ◽  
Autism Diagnostic Observation Schedule ◽  
Diagnostic Interview ◽  
Social Responsiveness ◽  
High Functioning ◽  
Autism Diagnostic Interview ◽  
Scale Scores ◽  
Behavior Rating Inventory ◽  
Autism Diagnostic Observation

AbstractAlthough circumscribed interests are pathognomonic with autism, much about these interests remains unknown. Using the Interests Scale (IS), this study compares interests between 76 neurotypical (NT) individuals and 109 individuals with high-functioning autism spectrum disorder (HF-ASD) matched groupwise on age, IQ, and gender ratio. Participants and their parents/caregivers completed diagnostic measures (the Autism Diagnostic Interview—Revised and the Autism Diagnostic Observation Schedule; HF-ASD only), cognitive tests (Wechsler IQ Scales), and questionnaires (the Repetitive Behavior Scale—Revised, the Behavior Rating Inventory of Executive Function, and the Social Responsiveness Scale), in addition to the IS. Consistent with previous research, HF-ASD and NT individuals did not differ in number of interest areas, but the types of interests and intensity of those interests differed considerably. Using only the IS intensity score, 81% of individuals were correctly classified (NT or HF-ASD) in a logistic regression analysis. Among individuals with HF-ASD, Interests Scale scores were significantly related to Autism Diagnostic Observation Schedule, Behavior Rating Inventory of Executive Function, Repetitive Behavior Scale—Revised, and Social Responsiveness Scale scores, but they were not related to Autism Diagnostic Interview—Revised scores, IQ, gender, age, or psychotropic medication use. The type and intensity, but not the number, of interests distinguish high-functioning individuals with ASD from NT individuals.

scholarly journals Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

2019 ◽  
Author(s):  
Diana C. Dima ◽  
Rachael Adams ◽  
Stefanie C. Linden ◽  
Alister Baird ◽  
Jacqueline Smith ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Copy Number ◽  
Genetic Factors ◽  
Copy Number Variants ◽  
Neural Correlates ◽  
Common Mechanism ◽  
Node Centrality ◽  
Neural Integration ◽  
Increased Risk ◽  
Theory Framework

AbstractRare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.

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