Autism and Genetic Mutations

Autism spectrum disorders (ASD) is a general term that encompasses a group of disorders that have as their point of origin anomalies in the development of the human brain.  The neurological symptoms that have been associated with ASD include: impairment of normal social development, difficulties with verbal and nonverbal communication and marked repetitive behaviors.  In terms of the latter symptom, anomalies in the brain circuits that are also implicated in obsessive compulsive disorder (OCD) have been identified.  The syndromes that fall within the general definition of ASD include autistic disorder, Rett syndrome, childhood disintegrative disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS) and Asperger syndrome. Paradoxically, certain individuals sometimes display uncanny abilities in visual skills, music, math and art.

In general, the disease is discovered in young children, usually between 2 and 3 years old.  ASD has been diagnosed in over 2 million individuals in the U.S. and many millions throughout the world.  Evidence obtained through the statistics compiled by the Center for Disease Control (CDC) indicates that the incidents of ASD are increasing.  The reasons for this are unclear.

What has been ascertained is that there is strong genetic component in this disease.  What makes ASD particularly refractory to the development of a definitive cure is that the molecular biology is quite complex and involves a multiplicity of genes.  In this report, the findings of Dr. Brian J O’Roak and his colleagues, from the Department of Genome Studies at the University of Washington in Seattle and other collaborating institutions, will be examined.

Autism spectrum disorders (ASD) is a general term that encompasses a group of disorders that have as their point of origin anomalies in the development of the human brain.  The neurological symptoms that have been associated with ASD include: impairment of normal social development, difficulties with verbal and nonverbal communication and marked repetitive behaviors.  In terms of the latter symptom, anomalies in the brain circuits that are also implicated in obsessive compulsive disorder (OCD) have been identified.  The syndromes that fall within the general definition of ASD include autistic disorder, Rett syndrome, childhood disintegrative disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS) and Asperger syndrome. Paradoxically, certain individuals sometimes display uncanny abilities in visual skills, music, math and art.

In general, the disease is discovered in young children, usually between 2 and 3 years old.  ASD has been diagnosed in over 2 million individuals in the U.S. and many millions throughout the world.  Evidence obtained through the statistics compiled by the Center for Disease Control (CDC) indicates that the incidents of ASD are increasing.  The reasons for this are unclear.

What has been ascertained is that there is strong genetic component in this disease.  What makes ASD particularly refractory to the development of a definitive cure is that the molecular biology is quite complex and involves a multiplicity of genes.  In this report, the findings of Dr. Brian J O’Roak and his colleagues, from the Department of Genome Studies at the University of Washington in Seattle and other collaborating institutions, will be examined.

In this exhaustive study, samples from 2446 ASD patients were used.  Of the 192 candidate genes, 44 genes were selected.  This selection was based on the determination to look at disruptive mutations, known associations with ADS-related symptoms, overlap with genes known to be involved in neurodevelopment and gene copy number variation (CNV).

A summary of the results of this work follows –

• Discovery of 27 de-novo genetic mutation events in 16 genes
• 59% of these mutations predicted to either shorten the protein gene products or disrupt the splicing that is required to yield functional protein products
• Recurrent disruptive mutations in six genes – CHD8, DYRK1A, GRIN2B, TBR1, PTEN AND TBL1XR1.  Five of these genes are contained within the catenin-chromatin-remodeling network.

This data confirms associations with specific genes and particular phenotypic expressions of ASD – CHD8 has been linked to macrocephaly and DYRK1A with microcephaly.  In addition, these results confirm the possible role of the catenin-chromatin-remodeling network - a critical network of genes and gene products involved in embryonic development.  However, these data do not establish an unambiguous causal relationship between these genetic anomalies and ASD.  This work represents an important contribution in the search for such direct causal link that may eventually lead to therapeutic relief for individuals with ASD.