Genetic Basis Of Autism Spectrum Disorder Research Articles

New insights into candidate genes for autism spectrum disorder in 8p23.1 duplication syndrome

The 8p23.1 duplication syndrome is a rare condition, characterized by dysmorphisms, intellectual disability, congenital cardiac anomalies, and autism spectrum disorder (ASD). The current model for explaining the pathogenesis of this condition postulates that few dosage-sensitive genes within the duplication are sufficient for the core clinical features, although the molecular mechanisms leading to the ASD presentation remain to be solved. Herein, we described clinical and cytomolecular findings of an 8p23.1 duplication in a boy with mild facial dysmorphisms, cardiac anomalies and ASD. Therefore, we investigated the influence of duplicated genes on the pathophysiology of ASD in our patient. We identified four duplicated genes (BLK, GATA4, PINX1, TNKS) connected with proteins previously associated with ASD and involved in significant enriched pathways associated with human neurological conditions. Moreover, the candidate genes are highly expressed in brain regions associated to ASD, such as the hippocampus. Taken together, these results point out crucial interactions among BLK, GATA4, PINX1, and TNKS and genes associated with ASD. We indicate cellular networks perturbations encompassing neuronal development pathways related to our patient's condition. Thus, these findings bring new insights into the genetic basis of ASD in patients with 8p23.1 duplication syndrome.

Influence of Gestational Chlorpyrifos Exposure on ASD-like Behaviors in an fmr1-KO Rat Model.

Based on previous reports, exposure to pesticides could be linked to the prevalence increase of autism spectrum disorders (ASD). Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents. However, ASD severity degree results from the complex relationship between genetic background and environmental factors. Thus, animals with a genetic vulnerability and prenatally exposed to CPF could have a more severe ASD-like phenotype. Fragile X syndrome is one of the most common monogenic causes of ASD, characterized by a mutation in the X chromosome which alters the expression of the fragile X mental retardation protein (FMRP). Based on this, some fmr1 knockout (KO) rodent models have been developed to study the physiological and genetic basis of ASD. Both fmr1-KO and wild-type male rats (F2 generation) were used in the present study. F1 pregnant females were randomly exposed to 1mg/kg/mL/day of CPF (s.c.) from GD12.5-15.5 or vehicle. Different behavioral, developmental, and molecular variables were analyzed in F2 males. KO rats were heavier, emitted altered USVs, were socially inefficient, reacted more to a novel stimulus, were hyperactive when exploring a new context, but hypoactive when exploring anxiety-inducing environments, and had an upregulated hippocampal expression of the grin2c gene. When exposed to low doses of CPF during gestation, these KO rats showed decreased climbing capacity, dysfunctional social interaction, and increased hippocampal expression for kcc1 and 5ht2c genes. Gestational CPF exposure increased the ASD-like phenotype in those animals with a genetic vulnerability, although its effect was less generalized than expected. It is the first time that this additive effect of CPF exposure and the fmr1-KO genetic vulnerability model is explored concerning social traits or any other behavior.

Searching for convergent pathways in autism spectrum disorders: insights from human brain transcriptome studies.

Autism spectrum disorder (ASD) is one of the most heritable neuropsychiatric conditions. The complex genetic landscape of the disorder includes both common and rare variants at hundreds of genetic loci. This marked heterogeneity has thus far hampered efforts to develop genetic diagnostic panels and targeted pharmacological therapies. Here, we give an overview of the current literature on the genetic basis of ASD, and review recent human brain transcriptome studies and their role in identifying convergent pathways downstream of the heterogeneous genetic variants. We also discuss emerging evidence on the involvement of non-coding genomic regions and non-coding RNAs in ASD.

Autism Spectrum Disorder Genetics

The last several years have seen unprecedented advances in deciphering the genetic etiology of autism spectrum disorders (ASDs). Heritability studies have repeatedly affirmed a contribution of genetic factors to the overall disease risk. Technical breakthroughs have enabled the search for these genetic factors via genome-wide surveys of a spectrum of potential sequence variations, from common single-nucleotide polymorphisms to essentially private chromosomal abnormalities. Studies of copy-number variation have identified significant roles for both recurrent and nonrecurrent large dosage imbalances, although they have rarely revealed the individual genes responsible. More recently, discoveries of rare point mutations and characterization of balanced chromosomal abnormalities have pinpointed individual ASD genes of relatively strong effect, including both loci with strong a priori biological relevance and those that would have otherwise been unsuspected as high-priority biological targets. Evidence has also emerged for association with many common variants, each adding a small individual contribution to ASD risk. These findings collectively provide compelling empirical data that the genetic basis of ASD is highly heterogeneous, with hundreds of genes capable of conferring varying degrees of risk, depending on their nature and the predisposing genetic alteration. Moreover, many genes that have been implicated in ASD also appear to be risk factors for related neurodevelopmental disorders, as well as for a spectrum of psychiatric phenotypes. While some ASD genes have evident functional significance, like synaptic proteins such as the SHANKs, neuroligins, and neurexins, as well as fragile x mental retardation-associated proteins, ASD genes have also been discovered that do not present a clear mechanism of specific neurodevelopmental dysfunction, such as regulators of chromatin modification and global gene expression. In its sum, the progress from genetic studies to date has been remarkable and increasingly rapid, but the interactive impact of strong-effect genetic lesions coupled with weak-effect common polymorphisms has not yet led to a unified understanding of ASD pathogenesis or explained its highly variable clinical expression. With an increasingly firm genetic foundation, the coming years will hopefully see equally rapid advances in elucidating the functional consequences of ASD genes and their interactions with environmental/experiential factors, supporting the development of rational interventions.