understanding autism through Genomic Analysis

Autism, the prototypic pervasive developmental disorder, usually evident by the age of three to four years, is defined by the following core symptoms:

• limited or absent verbal communication
• lack of reciprocal social interaction/responsiveness
• restricted, stereotypic, often ritualized patterns of behavior and/or interest.

Autism spectrum disorder (ASD) covers a broader range of symptom combinations, which also includes the less severe Asperger’s syndrome and pervasive developmental disorder not otherwise specified (PDD NOS). Intellectual disabilities coexist with ASD, but may be absent in Asperger’s syndrome.

Approximately 1 in 68 children have been diagnosed with ASD according to the data from US Centers for Disease Control (CDC) and this number is increasing. ASD exists in all socioeconomic, ethnic and racial groups, and is nearly 5 times more likely to affect boys than girls. It is highly heritable: among identical twins the concordance rate is 40-95% and in non-identical twins the concordance rate is 30% or more.

Treatment of core symptoms of ASD 

Autism is not a medical diagnosis. It is a “container” of several hundred or more diseases or developmental errors arising from genetic variations,  inherited or appearing anew (de novo). 

Knowing precisely what these variations are opens an opportunity to employ highly specific, individualized treatment and follow-up strategies. Next Generation DNA sequencing (NGS) followed by Clinical Genomics analysis allows to identify pathogenic variants responsible for core symptoms and comorbidities.  A decade of Genomic Medicine has already demonstrated its superior effectiveness and increased patient satisfaction compared to conventional approaches. 

Treatment of comorbidities

The ASD core symptoms vary in severity, rarely occur in isolation and are often associated with a number of comorbidities. The most common among them are intellectual disability (ID) and seizures. The former is seen in about 60% of ASD cases and the latter occurs in about 20-30% of ASD cases. Other common conditions associated with ASD are:

• Behavioral/psychiatric (ADHD, disruptive behavior, aggression)
• Sleep disturbances
• Gastrointestinal problems.

Pharmacotherapy with psychotropic and anti-epileptic medications is a mainstay treatment for ASD comorbidities. However, use of these drugs in children with ASD could be problematic due to their adverse effects. Muscle rigidity, restlessness or weight gain could significantly reduce medication adherence and clinical utility.

The solution to this problem is genetic data guided medication selection or Pharmacogenomics (PGx for short). It has been well demonstrated that PGx-guided prescribing can significantly reduce medication side effects while improving their effectiveness and patient adherence. You can find more on PGx on this website. 

Genetics of ASD

Genetic abnormalities associated with ASD include chromosomal aberrations, copy number variations and pathogenic variants in genes associated with nervous system development and functions. To date, deleterious variants in over 700 genes, both variants that were not present in both parents (de novo) and inherited, have been discovered using molecular techniques. Molecularly defined ASD is responsible for about 20% of all ASD cases.

Examples of several important genes harboring deleterious mutations responsible for ASD symptoms are shown below. These examples illustrate how genetic data can be used to guide treatment and medical follow up (surveillance) of patients with ASD.

CHD8

Pathogenic variants in CHD8,  Chromodomain Helicase DNA Binding Protein 8 gene have been associated with ASD.

SYMPTOMS may include gastrointestinal problems such as constipation, reduced bowel motility. Seizures may be present as well. There is a risk of malignancy.

APPEARANCE. Mutation carriers may have prominent supraorbital ridges, widely spaced eyes, small head or pointed chin.

TREATMENT goals should include seizure control and maintaining bowel motility. Pharmacogenetics should be used for medication selection to minimize side effects and improve adherence.

SURVEILLANCE for malignancy should be part of a routine medical follow up.

ADNP

ADNP, Activity Dependent Neuroprotector Homeobox gene has been associated with ASD.

SYMPTOMS include mood disorders, anxiety, temper tantrums, attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive disorder and sleep problems.

APPEARANCE. Mutation carriers may have prominent forehead, high hairline, outside corners of the eyes that point upward or downward, droopy eyelids, broad nasal bridge, thin upper lip, unusually shaped ears, hand and finger abnormalities, eye and vision abnormalities (eyes that do not point in the same direction), farsightedness and early appearance of primary (baby) teeth.

TREATMENT should target mood and  anxiety symptoms, temper tantrums, as well as attention deficit (ADD/ADHD), obsessive-compulsive behavior and sleep problems.Pharmacogenetics should be used for medication selection to minimize side effects and improve adherence.
Nutraceuticals known to interact with ADNP are quercetin (from oak bark) and Jin Fu Kang (traditional Chinese medicine).

SCN2A

SCN2A, Sodium Voltage-gated Channel Alpha Subunit 2 gene.

SYMPTOMS include seizure disorder (epilepsy) and reduction in size of a brain structure called cerebellum, which is involved in movement and balance coordination.

TREATMENT should be directed to seizure control. Examples of nutraceuticals known to interact with the SCN2A gene are genistein (found in soy products) and grape seed proanthocyanidins (found in grape seeds).Medication effectiveness vary greatly depending on the variants present in the SCN2A gene. Therefore, to be effective, medication  selection should be guided by pharmacogenetics (PGx).

ARID1B

ARID1B, AT-Rich Interaction Domain 1B gene. At least 13 ARID1B gene mutations have been identified in individuals with ASD.

SYMPTOMS. Mutation carriers often have intellectual disability (ID), significant speech problems and brain malformations that can be seen on imaging studies.

APPEARANCE. Excessive hair growth, coarse face, malformed ears, short stature, small, undeveloped 5th finger. Cryptorchidism, also known as undescended testicles, may be present in males. Boys who have had cryptorchidism that was not corrected in early childhood are at increased risk for developing cancer of the testicles. Abnormalities of the roof of the mouth, also known as Coffin-Siris syndrome 1, may be present. 

TREATMENT is symptomatic. Examples of medications and nutraceuticals known to interact with the ARID1B gene are antirheumatic agents and dietary fats. 

TBR1

TBR1, T-Box, Brain 1 gene.

SYMPTOMS. Intellectual disability (ID) and growth retardation.

APPEARANCE. Small head size and underdeveloped brain structures known as pons and cerebellum seen on brain imaging.

TREATMENT is symptomatic.  Examples of nutraceuticals are epigallocatechin gallate (found in tea), genistein (found in soy products) and zinc sulfate.

DYRK1A

DYRK1A, Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A gene.

SYMPTOMS are intellectual disability (ID), speech problems and anxiety. Weak muscle tone, foot abnormalities, and walking problems may also be present. Seizures may be present. 

APPEARANCE. Small head, bitemporal narrowing (size of the head above the eyebrows is narrow), deep-set eyes, large simple ears and a pointed nasal tip. 

TREATMENT is symptomatic and should include seizure control (if present).Examples of nutraceuticals known to interact with this gene are harmine, choline, epigallocatechin gallate, folic acid, Jin Fu Kang, methionine and resveratrol.