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 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.

Prevalence and determinants of motor stereotypies in autism spectrum disorder: A systematic review and meta-analysis

Autism ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 569-590 ◽  
Author(s):  
Cláudia Melo ◽  
Luís Ruano ◽  
Joana Jorge ◽  
Tiago Pinto Ribeiro ◽  
Guiomar Oliveira ◽  
...  
Keyword(s):  
Systematic Review ◽  
Autism Spectrum Disorder ◽  
High Functioning Autism ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Inclusion Criteria ◽  
High Functioning ◽  
Younger Age ◽  
Lower Intelligence

Stereotypies are frequently reported in people with autism spectrum disorder (ASD) but remain one of the less explained phenomena. We aimed to describe, through a systematic review and a meta-analysis, the prevalence of motor stereotypies in ASD and study the factors that influence this prevalence. Our literature search included MEDLINE, Scopus, and PsycINFO databases. Quality and risk of bias were assessed. Thirty-seven studies were included and the median prevalence of motor stereotypies in ASD was 51.8%, ranging from 21.9% to 97.5%. The most frequent determinants associated with a higher number of stereotypies in ASD were a younger age, lower intelligence quotient, and a greater severity of ASD. Moreover, gender did not seem to influence the prevalence of stereotypies. Meta-analytic analysis showed that lower IQ and autism diagnosis (independent of IQ) are associated with a higher prevalence of motor stereotypies (odds ratio = 2.5 and 4.7, respectively). Limitations of the reviewed literature include the use of convenience samples, with small sizes and heterogeneous inclusion criteria, and the predominance of high-functioning autism individuals.

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.

Social Communication and Structural Language of Girls With High-Functioning Autism Spectrum Disorder

2020 ◽  
Vol 51 (4) ◽  
pp. 1139-1155
Author(s):  
Jenny M. Burton ◽  
Nancy A. Creaghead ◽  
Noah Silbert ◽  
Allison Breit-Smith ◽  
Amie W. Duncan ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Adaptive Behavior ◽  
Social Communication ◽  
High Functioning Autism ◽  
Autism Spectrum ◽  
Vineland Adaptive Behavior Scales ◽  
High Functioning ◽  
Expressive Communication ◽  
Vineland Adaptive Behavior ◽  
Structural Language

Purpose The purpose of this study was to characterize social communication and structural language of school-age girls with high-functioning autism spectrum disorder (HF-ASD) compared to a matched group of girls who are typically developing (TD). Method Participants were 37 girls between 7;5 and 15;2 (years;months)—18 HF-ASD and 19 TD. Children completed the Test of Pragmatic Language–Second Edition (TOPL-2) and Clinical Evaluation of Language Fundamentals–Fifth Edition. Parents completed the Children's Communication Checklist–2 United States Edition (CCC-2) and Receptive and Expressive Communication subdomains of the Vineland Adaptive Behavior Scales–Second Edition. Results In the area of social communication, girls with HF-ASD earned significantly lower scores and were more often classified as having an impairment on the TOPL-2 and the CCC-2. However, 28% and 33% earned average scores on the TOPL-2 and the CCC-2, respectively. In the area of structural language, no significant differences were found between groups on Clinical Evaluation of Language Fundamentals–Fifth Edition indexes. In contrast, girls with HF-ASD earned significantly lower scores and were more often classified as having an impairment on the Vineland Adaptive Behavior Scales–Second Edition. Sixty-one percent and 83% scored below average on the Receptive and Expressive Communication subdomains, respectively. Conclusions It has been argued that girls with HF-ASD, when compared to boys with HF-ASD, may have advantages for social communication and structural language that mask their impairments. However, when compared to girls who are TD, girls with HF-ASD demonstrated impaired social communication and structural language. Clinicians should include and carefully examine multiple sources of information when assessing girls with HF-ASD.

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