Thursday 20 July 2023

Genetic testing results

Click on the picture above to read about the upcoming event in London. There are familiar faces appearing, like Agnieszka, Dr Boles and indeed me.


I am quite often sent genetic testing results. There are many types of tests ranging from inexpensive tests looking at SNPs to the expensive WES or WGS tests.

SNP = Snip = Single Nucleotide Polymorphism = a tiny genetic spelling mistake

WES = Whole Exome Sequencing

WGS = Whole Genome Sequencing

There is a small industry based around selling expensive supplements for SNPs.

We all carry thousands of SNPs and I think these tests may often raise issues that are not causal.  The results from WGS or WES can be much more insightful.  A good example being in the comment recently posted on this blog.


I've been following your blog for many years, it's a real blessing and the perfect place to come and read for us, parents of ASD kids. My boy, 9, has non-regressive autism, is largely non verbal (one word sentence) and has pronounced OCD symptoms (similar to excoriating disorder, but aimed at the environment), hyperactivity and severe gut problems, recurrent vomitting, gastroparesis, etc. The only thing that visibly stopped the hyperactivity and inappropriate laughing and helped him sit for longer periods of time and read his books or watch whole movies was 0.5/kg mg Naltrexone daily, as advised by this paper Lower doses saw the OCD creep back. As for his WGS test results, I've found relevant the fact that he has four pathogenic mutations in the EIF4EBP1, also a de novo mutation in the PIK3R1 gene and multiple other mutations in the STAT3, HTR3a, MAPT and also HLA-DRB1, HLA-DQA1, HLA-A, HLA-B, HLA-C, NRG1, NRG2, SCN4a, CACNA1S genes, amongst many others. We recently tried a course of Azythromycin for immuno-modulation, which saw his OCD reduced further, also his academic interest and focus increased visibly. He responds very well to Ibuprofen, AlkaSeltzer gold, Propranolol, Sytrinol and Cromolyn, but a quite long trial of Bumetanide two years ago did nothing for him. After all trials of various protocols and individual drugs, his gut is still bad, very often food seems to have major difficulty to pass though his digestive tract, no matter how finely tuned his diet is or how many prokinetics he takes. Given your extensive knowledge, I've always wondered what your take on the underlying problem/genetic pathway might be in his case (microglial activation, MTOR activation, perhaps?) and what drugs/cocktail of drugs might work best for his specific genetics and symptoms. He is a smart boy, has self-taught reading, loves music and masters his iPAD like a pro and, unlike what we know about autism, loves being around people. I cannot give up on him. We live in the UK, not the best place to even talk about treatments for autism. Please, if it's not too much to ask, tell me what other medications you thing it might boost his cognition further and help him start talking and develop more skills. Sorry for the long post. And thank you for any advice and ideas you might have to offer.


It would be useful to know which of the above mutations are present in at least one of the parents.  There so many possibly causal mutations here; I expect some are actually not relevant. In other words, it is not as scary at it may appear to be.

I do like to start with the easy part, which will be the ion channels.  Dysfunctions in ion channels (channelopathies) are often treatable with existing drugs and there is a great deal of information on each one.



This gene encodes the calcium channel Cav1.1.

This is known as an L type calcium channel, the other ones being Cav1.2 and Cav1,3 and Cav1.4.

These ion channels are extremely important to how your brain works.  Because they also play a role in how your heart works, numerous drugs have been developed, some are more specific to one type of channel (Amlodipine for Cav1.3, Verapamil for Cav1.2).

The individual channels interact with other sub-types, so a mutation in one sub-type can affect other subtypes.

Very interesting in this case are the GI problems. There were efforts made a few years ago to develop R-verapamil as a drug to treat IBS/IBD under the name of Rezular. Some readers of this blog have reported that the only thing that resolves their child’s GI problems is an L-type calcium channel blocker.

Note Memantine, which is an Alzheimer’s drug that was subject to a very large autism clinical trial in the US.  The trial was deemed a failure, but one reader told me that Memantine is the only drug she had found that solved her child’s GI problems.  Memantine has several different modes of action, and a little reported one is blocking L-type calcium channels.

Conclusions. Our results suggest that the neuroprotective effect of memantine could arise not only through the inhibition of the NMDA receptor current but also through the suppression of the L-type Ca2+ current.   


You might expect/hope a geneticist would suggest treatment with a drug like Verapamil.



This gene encodes the sodium ion channel Nav1.4.

This is one of the genes associated with Hypokalemic Periodic Paralysis (HPP), that was covered extensively in this blog. Interestingly the above Cav1.1 is also associated with Hypokalemic Periodic Paralysis (HPP).

The other genetic cause of HPP is KCNJ2 (an inward-rectifier potassium channel Kir2.1).

The immediate recovery therapy is drinking a potassium supplement.

A common preventative measure is acetazolamide (Diamox). This drug has also been covered in previous posts. The proposed mechanism is that it “increases the flow of potassium” – not sure what that is supposed to mean.

Some common anti-epilepsy drugs block Nav1.4 (Lamotrigine, Phenytoin etc).

All of the above-mentioned drugs have been used in autism. In specific cases they have shown a benefit.

You could ask your doctor to cautiously try them one by one.

Interestingly, the drug that seems to help many with sound sensitivity is Ponstan.  This cheap drug that affects the flow of potassium ions was proposed by Knut Witkowski as a therapy for 2-3 year olds to prevent non-verbal severe autism. 



Here you mention there are 4 pathogenic mutations.

This gene is a real mouthful, but regular reader might recall the odd looking eIF4E part appearing in some previous posts

“This gene encodes one member of a family of translation repressor proteins. The protein directly interacts with eukaryotic translation initiation factor 4E (eIF4E), which is a limiting component of the multi subunit complex that recruits 40S ribosomal subunits to the 5' end of mRNAs. Interaction of this protein with eIF4E inhibits complex assembly and represses translation. This protein is phosphorylated in response to various signals including UV irradiation and insulin signaling, resulting in its dissociation from eIF4E and activation of cap-dependent mRNA translation.”

eIF4E inhibitors for Autism – Why not Ribavirin?


As you can see in the above post there are numerous ways to block elF4E. It is possible that the 4 mutations in your gene EIF4EBP1 could have the reverse effect in which case you would want to activate elF4E, not block it.

On the list, in my post above, is quercetin which is OTC and simple to try.



A mutation in this gene can alter the PI3K/AKT/mTOR signaling pathway.

If this gene is causing a problem you might see some facial features a triangular face, a prominent forehead, small chin with a dimple, a loss of fat under the skin, prominent ears, hearing loss and delayed speech.

A mutation in this gene can lead to SHORT syndrome, which hopefully your pediatrician will have heard of.



STAT3 plays a key role in the immune system and elsewhere.

You can either have too much or too little STAT3.

In lay terms the immune system might end up either over-activated (hence benefiting from Ibuprofen and Cromolyn sodium) or under activated.

The immunomodulatory probiotics prescribed by gastroenterologists might be worth a try.

Lactobacillus rhamnosus GG

Lactobacillus plantarum 299v 


This might well reduce GI problems as well.



This gene encodes subunit A of the type 3 serotonin receptor. It has lots of effects, but it may contribute to the vomiting.

It is associated with:

  • Motion sickness
  • Irritable bowel syndrome
  • Social phobia
  • Serotonin syndrome

For gastroparesis (impaired stomach's motility) the good drug seems to be Domperidone, which you should be able to get for free from your NHS doctor.

Another very popular therapy for gut dysbiosis of all kinds in some countries, but not the UK, is sodium butyrate. This has been mentioned in previous posts. It is an OTC supplement that will produce butyric acid in the gut and it helps restore a healthy mucosa. If you eat lots of fiber and have a healthy microbiome you would produce butyric acid naturally. The cheapest place in Europe to buy it is Poland, where they sell a product called Intesta Max (a weaker version is Intesta).  In the UK it is 3 times more expensive. Making friends with a Pole will save you money.



The MAPT gene makes tau proteins.  There is a class of disease called tauopathy.

Tau Reduction Prevents Key Features of Autism in Mouse Models


Tau: A Novel Entry Point for mTOR-Based Treatments in Autism Spectrum Disorder?


As with the PIK3R1 mutation this will lead you to the idea of targeting mTOR signalling. You can inhibit this with Rapamycin, which has been used in autism.


Rapamycin/Sirolimus Improves the Behavior of an 8-Year-Old Boy With Nonsyndromic Autism Spectrum Disorder


One UK reader did get Everolimus prescribed on the NHS, but that was because the child was diagnosed with a genetic disorder called TSC. Several readers of this blog have tried Rapamycin as used in the Chinese case study.

If you do not have an over activated immune system, Rapamycin will cause the problem of an underactive immune system.



 These genes all play a role in the immune system.

The human leukocyte antigen (HLA) system is a complex of genes in humans which encode cell-surface proteins responsible for regulation of the immune system.

The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person and is therefore not an invader.


HLA Immune Function Genes in Autism

The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects.

One specific HLA gene has been studied in autism.

 Inheritance of HLA-Cw7 Associated With Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) is a behaviorally defined disorder that is now thought to affect approximately 1 in 69 children in the United States. In most cases, the etiology is unknown, but several studies point to the interaction of genetic predisposition with environmental factors. The immune system is thought to have a causative role in ASD, and specific studies have implicated T lymphocytes, monocytes, natural killer (NK) cells, and certain cytokines. The human leukocyte antigen (HLA) system is involved in the underlying process for shaping an individual’s immune system, and specific HLA alleles are associated with specific diseases as risk factors. In this study, we determine whether a specific HLA allele was associated with ASD in a large cohort of patients with ASD. Identifying such an association could help in the identification of immune system components which may have a causative role in specific cohorts of patients with ASD who share similar specific clinical features. Specimens from 143 patients with ASD were analyzed with respect to race and ethnicity. Overall, HLA-Cw7 was present in a much greater frequency than expected in individuals with ASD as compared to the general population. Further, the cohort of patients who express HLA-Cw7 shares specific immune system/inflammatory clinical features including being more likely to have allergies, food intolerances, and chronic sinusitis as compared to those with ASD who did not express HLA-Cw7. HLA-Cw7 has a role in stimulating NK cells. Thus, this finding may indicate that chronic over-activation of NK cells may have a role in the manifestation of ASD in a cohort of patients with increased immune system/inflammatory features.


The therapeutic implication would be to look at immunomodulatory therapy.

At the simple level you have NSAIDs like Ibuprofen, but then you have the more potent drugs used to treat psoriasis, arthritis, IBD etc.

If you saw Dr Arthur Krigsman, the autism gastroenterologist, I guess he would prescribe Humira.  This is an injection you take every few weeks.  That very well might help your son in many ways. He does also come to Europe for consultations. You would need a colonoscopy.

Some British parents take their autistic kids with GI problems to Italy for treatment. You could ask the Thinking Autism charity who they go to see. One of these doctors presented at their conference in London in 2019.  He used some of Krigsman’s slides in his presentation.



Neuregulin 1 and 2 are implicated in brain disorders. NRG1 is well known as a schizophrenia gene, but it has been shown to be miss-expressed in autism as well.

NRG2 also plays a role in many neurological conditions.  

Neuregulins in Neurodegenerative Diseases 

The downstream effect of NRG1 is on epidermal growth factor (EGF). There are expensive cancer drugs like Lapatinib that are inhibitors of EGFR. 

As I have written in my blog, disturbed growth factors is a recurring feature of autism. This is why son many autism genes are also cancer genes. Don’t worry, this does not mean everyone with autism is going to get cancer.



Try and find a doctor who is interested to treat your son.

I think you will make great strides by treating the GI problems that you see every day.

I did meet an UK autism mother at that conference in London in 2019 who was told by her doctor that her son’s GI problems would not be treated in the UK and she should look abroad. She went to Italy and solved his problems.  It sounds so bizarre, I would not have believed it to be possible, had I not been talking directly to the mother.  I did talk to the Italian gastroenterologist at that same event.  Contact Thinking Autism and ask who was the Italian who presented in 2019.