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Looking for Genetic Link to Autism

In some cases of ASD, the birth order makes no difference. It has been suggested that children who have ASD who are not first born may experience reduced access to resources because their parents' attention might be split between a child with ASD and their older sibling. In addition, the older sibling may overcompensate for a younger sibling with ASD and that may, in turn, hinder development.


Autistic spectrum disorder (ASD) represents a set of complex neurodevelopmental disorder with a large degree of heritability and heterogeneity. ASD describes a group of neurodevelopmental diseases. It is characterized by social communication impairment, repetitive behaviors, and restricted interests. In addition, several studies have looked at ASD-risk genes to find how they interact with other parts of the human genome. Because of the patchwork like pathophysiology targeted sequencing studies identified several high-confidence candidate genes. They also have noted influences of neuronal migration disorder in the genes. This study also found 67 ASD-risk genes. Although ASD is highly clinical and genetic patchwork some candidate genes, in fact, can define the clinical subtype of ASD. Investigating the relationship between phenotypes and genotypes deepen the understanding of ASD and assisting in clinical diagnosis and intervention. Characterization of their cerebral cortex laminar features revealed that network genes were highly expressed in different cortical layers. They identified novel risk genes and identified their associated brain expression features and biological networks. They facilitate the discovery of information necessary for accurate genetic counseling and testing (Li, et al, 2017).

A substantial genetic component accounts for ASD etiology, with some rare and common genetic risk factors recently identified. Large collections of DNA from thoroughly characterized ASD families are an essential step to confirm genetic risk factors, identify new variants, and investigate genotype-phenotype correlations. The Italian Autism Network (ITAN) aimed at constituting a clinical database and biorepository of samples derived from ASD subjects and first-degree relatives (mother, father, biologically related sister or brothers) extensively and consistently characterized by child psychiatry centers in Italy.
The study has led to an extensive collection of biological samples associated with standardized clinical assessments from a network of expert clinicians and psychologist. The database has information on 812 individuals from 249 families and samples for 98% of the subjects. ASD also previously referred to as Pervasive Developmental Disorder (PDD) are a group of neurodevelopmental disorders with onset in early childhood characterized by a triad of core symptoms, impaired social interaction, and communication and repetitive and narrow pattern of behaviors and interests.

Many neuropsychiatric conditions are symptoms are often present in addition to core symptoms in ASD. Most common are mental retardation (subaverage intellectual ability equivalent to or less than 70 that is accompanied by significant deficits in abilities [as in communication or self-care] necessary for independent daily functioning). It is usually present from birth or infancy and is manifested especially by delayed or abnormal development by learning difficulties and by problems in social adjustment, hyperactivity, epilepsy, or aggressive behaviors. PDD-NOS defines a subtype of autism characterized people on the spectrum but don't fully meet the criteria for other autism or other ASD. Asperger Syndrome is a less severe variant with no cognitive deficits or language impairment. One of the biggest problems with this study was putting all the different autistic disorders together under one umbrella like the DSM-V does. It implies all symptoms are needed to qualify as having ASD. The analysis of larger and in particular clinically well-characterized ASD samples is critical for the identification of new genetic variants and their validation for establishing of genotype-phenotype correlations. It found 49% of subjects had an IQ of 50-75 (Muglia et al. 2018).

Different cell types are also known to show different spatial-temporal distributions. Such complexities thus raise the unanswered questions: how much of the age-related molecular change in human brains is a direct consequence of the cell type composition change? Similar questions about the molecular changes in neural disorders, including autism, also remained unanswered [deconvolution] simplification of a complex signal 9as in instrumental data) usually by removal of instrument noise. Convolutions are the irregular ridges on the surface of the brain and especially of the cerebrum of higher mammals. In this study, they made use of a 2-step deconvolution procedure to estimate the cell type composition changes in the human brain after birth.

Transcriptome complete set of RNA transcribed from a particular genome. Age-related changes in the composition dependent and composition-independent component were applied to identify genes with age-related changes in either component. No overlap was noted between the two groups. Autism is a common neurodevelopmental disorder. Various studies have found upwards of 1775 genes with differential expression between autism cases and unaffected controls.
In this study, they attempted to investigate the role of changes related to or independent to cell type composition in the human brain development and pathogenesis of autism. They found the composition change to be the main source of age-related expression change in the human brain. It implies that the neuronal maturation is primarily factored creating an age-related expression, especially during the infant state. This study suggests that complexity growth of the communication system not only depends on increasing number of neurons but also greatly relies on enhanced inter-cellular communications which are also critical to neuronal network functions.

It found the estimated neuron proportions in autistic brains are significantly smaller than in healthy brains. This study paved the way for more exhaustive analysis regarding the contribution of cell type composition. Further application of this technology to characterized human brain development, aging, and pathology of neural disorders including autism would be sufficient to verify their observations (Yu & He, 2017).

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Intellectual disability (ID) or delayed psychomotor development are by far the most common reasons for referral to genetic services, and most severe forms are caused by single genetic defects. In Western populations where parental shared common ancestry is rare most affected individuals are of sporadic cases. In this study, epilepsy was observed in 62 members of the cohort. As judged by MRI results structural brain abnormalities are also common. Prominent signs of autism were only present in eight of the 219 families, involving five known and three unknown ID genes.

Autism is rare in patients with recessive forms of ID. In addition, SP2 mutations with autism and large head size is noteworthy because it has been reported that autistic children tend to have large brains. SP2 is a cell cycle regulator gene in which deletion leads to interruption of neurogenesis in embryonic and postnatal brains. In view of the rapidly growing capacity for whole genome sequencing, the detection of genetic variants is no longer a problem. The search for gene defects that cause or predispose to ID, including autism, has to remain a priority of research into neuropsychiatric disorders. And in Western populations, even the largest pilot studies may be too small for finding recessive disorders in a systematic fashion (Hu et al, 2017).

Theory of mind (ToM) or the ability to understand the mental states of the self and others follow a common developmental trajectory in typically developing (TD) children in that children's understanding of their own and others' desires, true and false beliefs (FB), emotions and other mental states undergoes considerable development during preschool period. At age of three most TD children do not display ToM on traditional behavior tasks. By four or five, however, the majority of TD children show an understanding of the beliefs and mental states of themselves and others. In autistic children, however, the development of ToM does not seem to follow this same trajectory. ASD is characterized by a patchwork of symptoms including socio-communicative impairments and a display of restricted and repetitive behaviors and interests. Majority of ASD children show a delay in ToM and delays or deficits among this population are inconsistent.
Descriptive statistics for child age, receptive language ability, gender, SCQ score (Lifetime social communication Questionnaire), and FB performance are shown. As expected the TD group performed significantly better than the ASD group on FB tasks. They noted a positive association was discovered between the presence of at least one older sibling and FB performance.. there was no identified difference between the TD group and those with ASD who had at least one older sibling. This study both confirmed other research having been done and extended prior research as well (Matthews, Goldberg, & Lukowski, 2013).

Work Cited
Hu. H et al. (2017). Genetics of intellectual disability in consanguineous families. Molecular Psychiatry. Macmillan Publishers Limited. https://doi.org/10.1038/s41380-017-0012-2

Li, J. et al. (2017). Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Molecular Psychiatry. Doi: 10.1038/mp.2017.140

Matthews, N.L., Godberg, W.A. & Lukowski, A.F. (2013). Theory of mind in children with Autism Spectrum Disorder: Do siblings matter? International Society of Autism Research. Doi:10.1002/aur.1308

Muglia, P. et al. (2018). Italian Autism Network (ITAN): A resource of molecular genetics and biomarkers investigations. [Not Peer-reviewed]. http://dx.doi.org/10.1101/306845

Yu, Q & He,Z. (2017). Comprehensive investigation of temporal and autism-associated cell type composition-dependent and independent gene expression changes in human brains. Scientific Reports, 7(4121). Doi: 10.1038/s41598-017-04356-7