Introduction

Early Intervention

Early diagnosis of autism with timely interventions have been shown to have major long-term benefits on

• Symptom reduction

• Skill development

Autism spectrum disorder (ASD) can sometimes be diagnosed in children between the age of 2 to 3 years old. With early intervention, some children with autism can make substantial progress to a degree that symptoms associated with autism spectrum can barely be noticed. This is because a young child's brain is still forming during this stage of development, meaning that the brain and associated behavior are more changeable compared to the development at older ages. Because of this changeability, treatments have a better chance of being effective and with longer term impacts. The sooner a autistic child receives proper clinical intervention, the greater the chance for improved learning and progress (1-5).

In fact, recent guidelines suggest starting an integrated developmental and behavioral intervention as soon as ASD is diagnosed or seriously suspected. However, it can be difficult to diagnose ASD in young children based on their limited expressed symptoms at an early age. Whole genome sequencing test may be a timely option to confirm that a genetic etiology is associated with ASD symptoms. The detection of a pathogenic genetic variant may enable a physician to obtain a timely diagnosis.

Co-Occurring Conditions

Over the last 10 years, large-scale genetic research has shown that autism spectrum disorder is caused by multiple genes and environmental factors. Plus, the disorder is often accompanied with overlapping disease conditions.

It is often difficult to distinguish which genes are conferring deleterious impacts associated with the common autism symptoms. For example, mutations in the UBE3A gene are associated with autism, but also with Angelman syndrome, a condition that is distinct from autism. However, children affected by Angelman syndrome show similar autistic symptoms such as movement and speech abnormalities, and physicians could misdiagnose the patients as affected by autism.

Determine Challenging Mutations Associated with Autism

To confirm autism and co-occurring conditions, accurate determination of pathogenic mutations in a large number of genes harboring difficult-to-detect gene variations is critical. Rainbow’s multi-genomic testing approach is unique because it enables simultaneous detections of multiple types of genetic mutations from the whole genome, resulted in rapid clarification of the genetic cause associated with the underlying disorder.

Challenging mutations include

• Copy number variants (CNVs), including intragenic and multi-gene CNVs

• Intronic mutations, including deep intronic variants

• Mosaic mutations, including mosaic CNVs

• Splice site variants

Our technology platforms include whole genome, RNA, Sanger, long-read sequencing, high-resolution microarray and high-density DNA array genotyping, to determine challenging mutations.

Genetics and Autism

• Although clinical symptoms of ASD can be highly variable, many studies have shown that ASD is highly heritable. That is, genetic risk factors are associated with the majority of the risks for ASD.

• Over the last 15 years, genomic studies have identified hundreds of ASD risk genes or loci, enabling the molecular diagnoses in 10%-35% of individuals with ASD. Specifically, diagnostic yield has been shown to be significantly higher in affected individuals with complex clinical presentations, that is, more positive reports are obtained from patients with additional co-morbidities that include intellectual disabilities, seizures, and other clinical features.

Spontaneous Genetic Mutations

• A recent large-scale study using whole genome sequencing data estimated that spontaneous genetic mutations, also known as de novo mutations, “contribute to 52%-67% of autism arising from low-risk families (with one child affected), and 30%-39% of cases of all autism” (Communications Biology. 2021, 4:1026).

  • These spontaneous, de novo mutations occurred with the child, and are not inherited from the parents

  • Rainbow whole genome sequencing test is designed to detect these complex de novo mutations, including intronic, splice site and mosaic mutations, which are challenging to determine.

  • Curated Gene List – Rainbow also curated over 1000 newly-reported autism genes with associated annotations to enable complex CNV and de novo mutation analysis in these novel autism genes.

Copy Number Variants (CNVs)

Copy Number Variants are submicroscopic structural changes in chromosomes that include duplications, deletions, translocations, and inversions.  Based on recent worldwide autism research, including studies in Asia, CNVs are important contributing factors in autism susceptibility. Whole genome sequencing with confirmation by RNA and Sanger sequencing, and high-resolution microarray (1.6Kb resolution) testing, allows for the determination of these small- and multi-gene CNVs.

Clinical Whole genome Sequencing

• In children with complex clinical presentations, such as autistic behavior coupled with signs of developmental delays, clinical whole genome sequencing has been shown to be effective in confirming a genetic cause.

Where Traditional Testing Failed to Detect a Genetic Cause

• Routine testing for Fragile X syndrome, karyotyping and chromosomal microarray (CMA, resolution at 50Kb) testing are commonly used by physicians as the first-tier diagnostic attempt for patients with autism spectrum disorder, however, a positive diagnosis is only obtained in approximately 1%, 5%, and 5-10% of the cases, respectively, using these three approaches. The other 90%-99% of cases remain unresolved and without a diagnosis, delaying the ability for a timely clinical intervention.

Whole Genome Sequencing, RNA Sequencing Coupled with High-Resolution Microarray Testing (Resolution at 1.6Kb)

• With the advent of whole genome sequencing coupled with copy number variant analysis capabilities, substantially higher diagnostic yields, from 15-20% (ASD only) to over 50% (ASD with additional symptoms such as developmental delay), have been reported.

• Many patients may also show a variety of neurological or behavioral phenotypes. Pathogenic variants associated with neurological or childhood psychiatric disorders will also be reported if these variants are detected from the whole genome data.

Specific Gene Analysis

Autistic Behavior & Autism Spectrum Disorder: Over 1400 genes, 366 associated co-occurring disorders

Attention Deficit Hyperactivity Disorder ADHD: 219 genes, 183 associated disorders

Test Descriptions

• The process starts with a physician office visit. The clinician will order the test for the patient.

• Clinical whole genome sequencing and other confirmation testing are performed at U.S. CAP-accredited or CLIA-certified laboratories. 

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