Dataset Information

Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder.

ABSTRACT: OBJECTIVE:Aside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes or loci. METHOD:Analyses preemptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains. RESULTS:Children with de novo mutations (N=112) had a greater likelihood of motor delay during early development (later age at walking), but they were less impaired on certain measures of ASD core symptoms (parent-rated social communication abnormalities and clinician-rated diagnostic certainty about ASD) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language (i.e., regular use of complex sentences). CONCLUSIONS:Children with ASD with de novo mutations may exhibit a "muted" symptom profile with respect to social communication and language deficits relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental and demographic variables are properly accounted for first.

SUBMITTER: Bishop SL

PROVIDER: S-EPMC5578709 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder.

Bishop Somer L SL Farmer Cristan C Bal Vanessa V Robinson Elise B EB Willsey A Jeremy AJ Werling Donna M DM Havdahl Karoline Alexandra KA Sanders Stephan J SJ Thurm Audrey A

The American journal of psychiatry 20170303 6

<h4>Objective</h4>Aside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes o ...[more]

PMID: 28253736

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Project description:Autism spectrum disorder (ASD) and congenital heart disease (CHD) are linked on a functional and genetic level. Most work has investigated CHD-related neurodevelopmental abnormalities. Cardiac abnormalities in ASD have been less studied. We investigated the prevalence of cardiac comorbidities relative to ASD genetic contributors. Using high frequency ultrasound imaging, we screened 9 ASD-related genetic mouse models (Arid1b(+/-) , Chd8(+/-) , 16p11.2 (deletion), Sgsh(+/-) , Sgsh(-/-) , Shank3 Δexon 4-9(+/-) , Shank3 Δexon 4-9(-/-) , Fmr1(-/-) , Vps13b(+/-) ), and pooled wild-type littermates (WTs). We measured heart rate (HR), aorta diameter (AoD), thickness and thickening of the left-ventricular (LV) anterior and posterior walls, LV chamber diameter, fractional shortening, stroke volume and cardiac output, mitral inflow Peak E and A velocity ratio, ascending aorta velocity time integral (VTI). Mutant groups presented small-scale alterations in cardiac structure and function compared to WTs (LV anterior wall thickness and thickening, chamber diameter and fractional shortening, HR). A greater number of significant differences was observed among mutant groups than between mutant groups and WTs. Mutant groups differed primarily in structural measures (LV chamber diameter and anterior wall thickness, HR, AoD). The mutant groups with most differences to WTs were 16p11.2 (deletion), Fmr1(-/-) , Arid1b(+/-) . The mutant groups with most differences from other mutant groups were 16p11.2 (deletion), Sgsh(+/-) , Fmr1(-/-) . Our results recapitulate the associated clinical findings. The characteristic ASD heterogeneity was recapitulated in the cardiac phenotype. The type of abnormal measures (morphological, functional) can highlight common underlying mechanisms. Clinically, knowledge of cardiac abnormalities in ASD can be essential as even non-lethal abnormalities impact normal development. LAY SUMMARY: Autism spectrum disorder (ASD) and congenital heart disease (CHD) are linked functionally and genetically. ASD cardiac phenotyping is limited. We assessed the cardiac phenotype of 9 ASD-related mouse models. We found subtle heterogenous cardiac abnormalities compared to controls, with more differences within ASD than between ASD and controls, mirroring clinical findings. Clinically, knowing the cardiac abnormalities in ASD is vital as even non-lethal cardiac abnormalities can impact development.

Project description:Gastrointestinal (GI) symptoms are frequently reported in children with autism spectrum disorder (ASD). We evaluated the frequency and severity of GI symptoms in preschool-aged children with ASD compared to participants with typical development (TD). Our goal was to ascertain whether GI symptoms are associated with differences in sex or developmental and behavioral measures. Participants were between 2 and 3.5 years of age and included 255 children with ASD (184 males/71 females) and 129 age-matched TD controls (75 males/54 females). A parent interview was used to assess GI symptoms (abdominal pain, gaseousness/bloating, diarrhea, constipation, pain on stooling, vomiting, difficulty swallowing, blood in stool or in vomit). Children with GI symptoms in each diagnostic group were compared to children without GI symptoms on measures of developmental, behavioral, and adaptive functioning. GI symptoms were reported more frequently in children with ASD compared to the TD group (47.8% vs. 17.8%, respectively). Children with ASD were also more likely to experience multiple GI symptoms (30.6% vs. 5.4%). GI symptoms were equally common in males and females across both diagnostic groups. There were no statistically significant differences in developmental or adaptive measures based on presence of GI symptoms in either ASD or TD children. Co-occurring GI symptoms were, however, associated with increased self-injurious behaviors, restricted stereotyped behaviors, aggressive behaviors, sleep problems and attention problems in both ASD and TD children. In children with ASD, a higher number of GI symptoms was associated with an increase in self-injurious behaviors, somatic complaints, reduced sleep duration, and increased parasomnias. LAY SUMMARY: ASD is characterized by challenges in social communication and repetitive behaviors. But, people with autism have many other difficulties including gastrointestinal problems. Children with ASD were three times more likely to experience GI symptoms than typically developing peers. Increased GI symptoms are associated with increased problem behaviors such as sleep problems, self-injury, and body aches. Since GI symptoms are often treatable, it is important to recognize them as soon as possible. Both clinicians and parents should become more aware of the high occurrence of GI problems in autistic people. Autism Res 2020, 13: 1778-1789. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

Project description:Background: In motor imitation, taking a partner's perspective often involves a mental body transformation from an embodied, ego-centered viewpoint to a disembodied, hetero-centered viewpoint. Impairments of both own-body-transformation (OBT) and abnormalities in visual-spatial processing have been reported in patients with neurodevelopmental disorders including autism spectrum disorder (ASD). In the context of a visual-motor interactive task, studying OBT impairments while disentangling the contribution of visual-spatial impairments associated with motor coordination problems has not been investigated. Methods: 85 children and adolescents (39 controls with typical development, TD; 29 patients with ASD; 17 patients with developmental coordination disorder, DCD), aged 6-19 years, participated in a behavioral paradigm in which participants interacted with a virtual tightrope walker (TW) standing and moving with him. The protocol enables to distinguish ego-centered and hetero-centered perspectives. Results: We show that (1) OBT was possible but difficult for children with neurodevelopmental disorders, as well as for TD children, when the task required the participant to perform a mental rotation in order to adopt a hetero-centered perspective. (2) Using multivariate models, hetero-centered perspective score was significantly associated with age, TW orientation, latency, and diagnosis. ASD and TD groups' performances were close and significantly correlated with age. However, it was not the case for DCD, since this group was specifically handicapped by visual-spatial impairments. (3) ASD and DCD did not perform similarly: motor performance as shown by movement amplitude was better in DCD than ASD. ASD motor response was more ambiguous and hardly readable. Conclusion: Changing perspective in a spatial environment is possible for patients with ASD although delayed compared with TD children. In patients with DCD, their visual-spatial impairments negatively modulated their performances in the experiment.

Dataset Information

Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder.

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Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder.

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