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The ARHGEF6 Gene: Assessing the Risk for Autism

ground-breaking study at The Great Plains Laboratory, Inc. pinpoints a mutation of the ARHGEF6 gene as a major cause of autism and a major reason for the male preponderance of autism.

Study Overview

Matt Pratt-Hyatt, Ph.D. and William Shaw, Ph.D., researchers at The Great Plains Laboratory, Lenexa, KS, Rebecca A. Haeusler, Ph.D., a professor in the Department of Pathology and Cell Biology, Columbia University, New York, NY, and Kobe C. Yuen Ph.D., a researcher at the Stowers Institute for Medical Reseach, Kansas City, MO published the identification of a major gene implicated as a cause of autism: Pratt-Hyatt et al., Hereditary Genetics 2018, 7:2, DOI: 10.4172/2161-1041.1000196

The Great Plains Laboratory organized the study utilizing volunteers as well as patient samples from the Autism Genetic Resource Exchange (AGRE), which is a program funded by Autism Speaks. In the study, the researchers genotyped 252 single nucleotide polymorphisms (SNPs) in 35 different genes that had previously been identified as autism risk candidate genes. This study was performed with 247 controls (106 male and 141 female) and 155 patients on the autistic spectrum (134 male and 21 female).  They found the most significant marker for autism of the 252 SNPs tested was a genetic variation called rs2295868 in the ARHGEF6 gene on the X chromosome. The odds ratio for males with this SNP was 4.09 with a p value <0.0003, which means nearly 80% would likely develop autism at some point in their lives. This is higher than any other single SNP previously evaluated for autism risk.

The odds ratio for females (1.02) for the same SNP was not statistically significant and did not indicate that this SNP increased the risk of autism for females. Since the ARHGEF6 gene is on the X chromosome, this research helps to explain the excess ratio of autism in males, such that males are 4.5 times more affected with autism than females. Males receive an X chromosome only from their mothers while females receive an X chromosome from both their fathers and mothers. Thus, mothers will transmit the affected gene to their sons while both mother and father may transmit the affected gene to their daughters. However, 20% of males with the affected gene do not appear to develop autism, although they may be at risk for schizophrenia and inflammatory bowel disorders. The ARHGEF6 gene SNP was found in 30% of the males with autism spectrum disorders meaning that 70% of cases of autism spectrum disorder in males are due to other causes. A negative result for the ARHGEF6 gene SNP does not rule out a child developing autism from other genes or other non-genetic causes.

The ARHGEF6 Gene, Dendritic Spines, Behavior, Learning, and Autism

Dendrites are the parts of neurons that receive information in the form of electrical impulses from the environment or other parts of the body and also transmit electrical signals via axons to other parts of the nervous system. According to Alvarez and Sabatini, a dendritic spine (or spine) is a small membranous protrusion from a neuron’s dendrite that typically receives input from a single axon at a synapse, the gap at the terminal end of the axon where electrical impulses stimulate neurotransmitters. The neurotransmitters cross the gap at the synapse called the synaptic cleft and excite nearby dendrites.

Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron’s cell body. Most spines have a bulbous head (the spine head), and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.

DendriticSpine.png

Dendritic spines express glutamate receptors. Spine plasticity is associated with motivation, learning, and memory. In particular, long-term memory can be affected by the growth of new dendritic spines (or the enlargement of pre-existing spines) to reinforce a particular neural pathway. The cytoskeleton of dendritic spines is particularly important because without a dynamic cytoskeleton, spines would be unable to rapidly change their volumes or shapes in responses to stimuli. These changes in shape might affect the electrical properties of the spine. The cytoskeleton of dendritic spines is primarily made of filamentous actin (F-actin). Enzymes such as the one produced by the ARHGEF6 gene, rapidly modify this cytoskeleton.

The repetitive behaviors common in autism might reflect the inability to rapidly remodel spines to learn new behaviors. Such findings are consistent with an emerging hypothesis that the brains of individuals with ASD are characterized by over-connectivity in local circuits and reduced connectivity between regions in different parts of the brain. This hypothesis helps to explain the tendency of many people with autism to desire the same routines and to have resistance to change.

TREATMENT OPTIONS FOR THE ARHGEF6 GENE MUTATION

Studies have shown that patients with autism have lower amounts of Fibroblast Growth Factors (FGF) and there are reports that patients undergoing FGF therapy have shown positive results. Because of the link between FGF and ARHGEF6, there may be some benefit for this type of therapy for people with autism. Dr. Luis Aguilar of Mexico has been utilizing this type of treatment for about 20 years and has reported extensive improvement in behavior and speech for patients undergoing this treatment. However, The Great Plains Laboratory has not evaluated Dr. Aguilar’s treatment or his claims of efficacy.

If you or child is positive for the ARHGEF6 gene SNP, it is not a definitive diagnosis of an autism spectrum disorder. It simply means there is a greater risk of developing an autism spectrum disorder. There are many things that can be done to potentially counteract various symptoms and common health problems associated with an autism spectrum disorder. The Great Plains Laboratory, Inc. has specialized in these kinds of specialty diagnostics for more than 20 years, and we recommend treatment strategies that are evidence-based and have a high level of efficacy for many patients. We recommend you partner with a healthcare practitioner who thoroughly understands this biomedical approach to an autism spectrum disorder.  You may contact our laboratory to request a list of these kinds of practitioners in your area.

Genetic susceptibility to an autism spectrum disorder may determine who develops this complex disorder, but factors like nutrient deficiencies, food allergies, toxin exposure, and pathogenic intestinal microbial overgrowth strongly influence the severity of symptoms. Yeast (most commonly, Candida) bacteria (particularly Clostridia), and toxins (both metal and non-metal) all have the potential to act as pathogens. Comprehensive laboratory testing can identify the physiological imbalances that contribute to an autism spectrum disorder and point to an individualized treatment approach. Many of the tests are urine tests and can be run on the same urine sample. Treatments are designed to restore the body to balance and optimize function through nutritional support, diet, detoxification, and reduction of toxic environmental influences. For information and resources, go to www.greatplainslaboratory.com/autism-spectrum-disorders.


FAQs: Autism Spectrum Disorder Risk Assessment

If you’re not able to find the answer to your specific question(s) here, please send an e-mail to autismrisk@gpl4u.com and one of our experts will respond to you as soon as possible.

How do I order the ARHGEF6 test?

This test is offered exclusively from The Great Plains Laboratory, Inc.  Tests can be ordered through physicians (MD, DO, ND, PA, or NP only) or certified genetic counselors. 

GPL will be building a referral database of physicians who can order and interpret this test.  In the meantime, to find a pediatric special needs physician in your area, visit the Medical Academy of Pediatric Special Needs (MAPS) web site, https://www.medmaps.org/clinician-directory/ to find member physicians by state.  Please note these physicians are not guaranteed to be able to order this test.  Physicians will also have their own fees for ordering and interpreting tests.  Please contact them to inquire about fees.

This test is not available in the state of New York. 

I am a Pediatric Special Needs Physician and I’m Interested in Joining the Referral List for test Ordering and Interpretation. How do I join?

Please contact your assigned GPL sales representative, send an e-mail to sales@gpl4u.com, or call the lab at (913) 341-8949.

How do I find a genetic counselor?

You may seek a genetic counselor through the National Society of Genetic Counselors at www.nsgc.org or through the American Board of Genetic Counseling at www.abgc.net.

What is the ARHGEF6 gene?

ARHGEF6 is a gene located on the X chromosome position 26.3 that codes for an enzyme called Guanine Nucleotide Exchange Factor 6. Diseases or non-disease related traits that are transferred through the X-chromosome are termed “sex-linked”. This enzyme is present in the brain, immune system, and the intestine. In the brain, its highest concentration is in the hippocampus CA1 region, which is important for new memory formation. ARHGEF6 is also responsible for normal neuron growth patterns. ARHGEF6 helps to control neurological spine and neurite growth morphologies. Because of its role in neuronal growth, loss of ARHGEF6 activity results in a decrease in the density of cortical pyramidal neurons. These mismanaged growth morphologies can lead to deficits in autophagy (the breakdown and recycling of cellular components) in microglia and impaired synaptic pruning, which have been linked to behaviors similar to those of ASD.

The ARHGEF6 enzyme also plays a role in immunity. It is present in large amounts in the immune system, especially in T-cells. In the intestine it may play a different role. Studies have shown that ARHGEF6 interacts with strains of bacteria that play a role in inflammatory bowel disease.

ARHGEF6’s role in immunity may help explain the link between environmental exposures and the increasing rates of an autism spectrum disorder spectrum disorder. As we are exposed to more toxic chemicals more every day, males with this mutation may be more susceptible to inflammation caused by toxin exposure. Since 20% of males who tested positive for the gene do not have an autism spectrum disorder spectrum disorder spectrum disorder, knowledge about these “resistant” males undoubtedly will help to find out how to protect the 80% of males that are susceptible to the gene.

How does this gene relate to the much higher incidence of an autism spectrum disorder in males compared to females?

Males receive an X chromosome from their mothers who have 2 X chromosomes while females receive an X chromosome from both their fathers and their mothers. Thus, mothers will transmit the affected gene to their sons while both fathers and mothers transmit the affected gene to their daughters.

X-Linked Recessive Inheritance.jpg

How common are mutations in this specific gene?

This mutation is present in about 15% of the population and is present more than twice as often in females than in males because females have two X chromosomes compared to one in males. Our studies so far find no link to the ARHGEF6 mutation and an autism spectrum disorder in females. However our number of female patients was limited. Therefore, no conclusions from this study can be made about how this gene affects human health in females. As we accumulate more data on females we will include it on our website.

What types are illnesses are associated with mutations to this gene?

Studies have linked many different health issues with ARHGEF6 mutations. In the intestine, mutations in ARHGEF6 have been associated with several types of diseases. ARHGEF6 has been associated with inflammatory bowel disease, ulcerative colitis, and Crohn’s disease. Mutations in ARHGEF6 can cause major structural changes to the brain and have been linked to an autism spectrum disorder spectrum disorder, mental deficiencies, and schizophrenia.

Who should have this gene tested? 

  • Women who are thinking about getting pregnant or who are pregnant

  • Males or females with a history of an autism spectrum disorder in their family

  • Anyone concerned about having a child with an autism spectrum disorder 

What can I do if I or my child tests positive for the ARHGEF6 gene SNP?

If you or child is positive for the ARHGEF6 gene SNP, it is not a definitive diagnosis of an autism spectrum disorder. It simply means there is a greater risk of developing an autism spectrum disorder. There are many things that can be done to potentially counteract various symptoms and common health problems associated with an autism spectrum disorder. The Great Plains Laboratory, Inc. has specialized in these kinds of specialty diagnostics for more than 20 years, and we recommend treatment strategies that are evidence-based and have a high level of efficacy for many patients. We recommend you partner with a healthcare practitioner who thoroughly understands this biomedical approach to an autism spectrum disorder.  You may contact our laboratory to request a list of these kinds of practitioners in your area.

Genetic susceptibility to an autism spectrum disorder may determine who develops this complex disorder, but factors like nutrient deficiencies, food allergies, toxin exposure, and pathogenic intestinal microbial overgrowth strongly influence the severity of symptoms. Yeast (most commonly, Candida) bacteria (particularly Clostridia), and toxins (both metal and non-metal) all have the potential to act as pathogens. Comprehensive laboratory testing can identify the physiological imbalances that contribute to an autism spectrum disorder and point to an individualized treatment approach. Many of the tests are urine tests and can be run on the same urine sample. Treatments are designed to restore the body to balance and optimize function through nutritional support, diet, detoxification, and reduction of toxic environmental influences. For information and resources, go to www.greatplainslaboratory.com/autism-spectrum-disorders.

I am concerned about discrimination against me and/or my child based on the information in the ARHGEF6 SNP test. What are current legal protections in the USA?

An excellent description of the laws in the USA regarding genetic discrimination is found on the website of the National Society of Genetic Counselors: http://aboutgeneticcounselors.com/Portals/0/NSGC%20GINA%20Fact%20Sheet%20Feb%202018%20-%20FINAL.pdf?ver=2018-03-09-151406-813&timestamp=1520631152656

At the present time, we do not know what safeguards against discrimination based on genetic testing are available in other countries.

What forms are required to get this test?

Forms that must be completed and submitted are:

  • Test Requisition Form (TRF)

  • Patient/Guardian Informed Consent

How do I collect a sample? 

  • The sample is collected with a buccal swab which is very similar to a Q-tip®.

  • Rinse your mouth with cold water before you begin collecting your sample and then swallow to remove excess saliva.

  • Collect sample by rubbing the insides of the cheeks of the mouth on all three swabs.

  • Place the swab sleeves containing the dry swabs in the paper envelope included in the kit.

  • Label the envelope with your name and date of sample collection.

  • Ship the test kit back to the laboratory using the shipping mailer provided.

  • More detailed instructions can be found on our website and in the test kits.

How long will it take to get my results?

Results will be available in about 4 weeks.

Will my test results be kept confidential? 

Results are kept confidential according to HIPAA requirements and will only be shared with the patient/guardian and designated healthcare practitioner or genetic counselor who authorized the test.  Results are sent via secure portal or secure e-mail. 

Who will have access to my results and how will they be used?

Results will only be shared with you as the patient/guardian and healthcare practitioner or genetic counselor who authorized the test. After 60 days, samples will be de-identified in our system and may be used for future research.

What is the significance of this test if my son is positive for the ARHGEF6 gene SNP?

In the study by The Great Plains Laboratory, Inc., 80% of males with the ARHGEF6 gene mutation had an autism spectrum disorder while 20% of males with the ARHGEF6 gene mutation did not develop an autism spectrum disorder. Thus, a baby boy with this gene mutation will have four times the risk of developing an autism spectrum disorder compared to a baby boy who is negative for this gene mutation. Since the development of an autism spectrum disorder decreases markedly with age, boys who are positive for this gene mutation would be expected to have decreased risk of an autism spectrum disorder as they age; new development of an autism spectrum disorder is rare after 5 years of age. However, non-autistic men with the ARHGEF6 gene mutation may have a higher rate of depression, colitis, or other bowel disorder.

Males with this gene who produce children do not transfer this gene to their sons but will transfer the gene to all of their daughters. However, our data so far are insufficient to know whether the presence of one or two of the ARHGEF6 gene mutations in female children increases their risk of developing an autism spectrum disorder.

What is the significance of this test if my son is negative for the ARHGEF6 gene SNP?

Males who are negative for this gene SNP will not develop an autism spectrum disorder or other illnesses associated with this gene SNP. However, they could develop an autism spectrum disorder or other illnesses due to other untested genetic factors or environmental factors. About 66% of patients with an autism spectrum disorder did not possess the mutant ARHGEF6 gene.

What is the significance of this test if a mother or her daughter is positive for the ARHGEF6 gene SNP?

Currently, we have insufficient data to know if females with one or two of the ARHGEF6 gene mutations have an increased risk of developing an autism spectrum disorder or any other illness associated with the ARHGEF6 gene mutations.

Females who have two of the ARHGEF6 gene mutations who bear children have an increased risk of having a boy with an autism spectrum disorder. If a woman with two of the gene mutations (homozygous) is pregnant with a boy child, there is a 100% risk that the boy child will receive the ARHGEF6 gene mutation and an 80% risk that the child will develop an autism spectrum disorder.

Females who have one of the ARHGEF6 gene mutations who bear children have an increased risk of having a boy with an autism spectrum disorder. If pregnant with a boy child, women with one of the ARHGEF6 gene mutations (heterozygous) will have a 50% risk that the boy child will receive the ARHGEF6 gene mutation and a 40% risk that the child will develop an autism spectrum disorder. 

At this time, our data are insufficient to know if women with one or two of the ARHGEF6 gene mutation genes are also at increased risk of having girls with an autism spectrum disorder or other illnesses such as inflammatory bowel disease and depression.

Who should I contact if I have more questions about this test?

Due to the highly technical and sensitive nature of this test, we ask that you connect with one of our genetic testing experts for any additional questions or concerns.  Please send an e-mail to autismrisk@gpl4u.com and one of our experts will respond as soon as possible. 


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