What Genetic Tests For My Intellectually Disabled Son?

My son is profoundly intellectually disabled.

What genetic tests would you want run for a case of intellectual disability?

This is a serious and honest question of immediate and critical importance to me personally. If you have an answer or other suggestions please reach out!

Here are the highlights:

• My son is profoundly intellectually disabled.

• Karyotype for fragile X and CMA have been run.

• I need to know what else could or should be run.

• You can email at new@sgenomics.org

For anyone else… here’s the rest of the journey. Perhaps it’s an interesting case study in clinical genetics if nothing else. It may also explain why I sometime complain about certain clinicians…

Background

My sons intellectual disability is one of the reasons I take a lack of adoption of genetic testing somewhat seriously and personally.

Aside from having spent essentially my entire career working on DNA sequencers and related tools. I’ve now also had to directly interact with clinicians who have often shown little interest in using these tools.

So… some background on my son. When I say my son is intellectually disabled I often suspect people think “a little delayed” or… perhaps they just don’t know what to think…

So in specific terms, this is what it means:

• He is 6 years old and non-verbal. Has limited auditory comprehension.

• He has extremely limited ability to communicate through non-verbal means (can point in limited contexts, can not use communication cards).

• Using standard tests, he has no measurable IQ.

• He can’t really concentrate or effectively play with most toys.

• His diet is limited.

• He can be violent. Both in terms of self harm and harming others.

• He has trouble sleeping.

• He is a wonderful, generally happy and energetic child and I love him dearly.

Doctors and Testing

As you can imagine it has been obvious that he has developmental issues for some time. First we went to Chiba Children’s Hospital. Japan has a pretty well developed health care system, and this is the largest children’s hospital in our county (Chiba)¹.

The Head of Child Psychiatry here said essentially the Japanese equivalent of “You can’t cure disability so there’s nothing I can do”².

I said are there no genetic tests available? He said No… I said I was pretty sure this wasn’t the case.

This made it clear to me that when I visit a clinician, it’s best to come prepared.

The next time I visited I took the time to do some research. Luckily there are several nice papers with flow charts outlining diagnostic processes:

In particular it was clear from the literature that fragile X and chromosomal microarray testing are standard recommendations that should be performed in all cases³.

The fact that testing for fragile X had not even been mentioned, given that it’s the leading cause of inherited intellectual disability was a concern. And I consider grossly negligent…

I emailed a few clinician-researchers in Japan whose work I’d read and asked where I could get fragile X testing done in Japan. They told he that any large hospital should be able to do this. For example in Chiba, Chiba University Hospital or… Chiba Children’s Hospital.

The next time we visited Chiba Children’s Hospital the Head of Child Psychiatry was subjected to the best angry rant in broken Japanese I could manage as as I aggressively stabbed the flowchart above demanding further tests…

2 Minutes later I was talking to a Medical Geneticist. She had an office across the hall, the Head of Child Psychiatry just and deemed it unnecessary to introduce us.

She agreed to run a Karyotype. This came back normal after a few weeks. Then a chromosomal microarray was run. This can back… well she said nothing. There were 3 loss regions. One of which is covered by 17 annotations. I could find at least one publication implicating a de novo micro deletion of two of the referenced genes (PAPOLG, REL) in a case intellectual disability.

I have no background in chromosomal microarray’s⁴ and don’t know how much to trust these results.

Having performed the “standard” tests. We were referred to a national genomics project.

They took blood draws from us (a trio)… and said they’d do something and we’d hear something. Sometime.

That was about a year ago.

After our experience at Chiba Children’s Hospital we moved to Chiba University Hospital⁵.

Here I reiterated my desire to have an accurate diagnosis and⁶ when pressed, the Child Psychiatrist here referred us to Neuroimaging, and for Metabolic testing⁷.

And of course I asked about genetic testing again... they said just wait for the results…

A few months later we get a call from the clinical genetics department. And have been asked to come in and sign more content forms. It seems nothing has happened this the original trio that was collected.

It’s not at all clear what they plan to do… “we just send the samples of the University of Nagoya” seems to be the standard response.

But I’ve learnt the hard way it’s best to come prepared, and perhaps will ask to visit Nagoya if it comes to that.

So… I’ll be doing my best to read the literature. But you can also help…

So What Next?

As it turns out I have a newsletter to which a few hundred people in genomics industry subscribe (that’s you). Hopefully among you is someone who can help me or someone who knows someone who can help me⁸.

Any advice is welcome but in particular which genetic tests are recommended for intellectual disability? There are certainly a ton of intellectual disability panels. Are these any good? Do you have any recommendations?

If a whole genome sequence was available what analysis should be performed?

The Genomics England Panel App has a large number of entries for intellectual disability… but what would you do with them?

I’m not expecting miracles. I’m not expecting a “cure” (there is no known effective treatment for intellectual disability). I’m not even with high probably expecting to identify a cause for my sons intellectual disability.

But I would like to make a best effort to understand my sons condition.

You can reach out via email (new@sgenomics.org) or post a comment below.

Tweets, likes etc. are also most welcome and could help my question reach someone who can help.

If nothing else perhaps this helps explain why I believe clinical adoption of sequencing technologies is going to be an uphill struggle.

Thank you for reading.

1. To get an appointment here, you need to call ~100 times in the 1 hour window per month that appointments can be scheduled. This took 2 months after we had a referral letter.

2. Aside from prescribe things like Aripiprazole for irritability.

3. Yes, I’m a sequencing absolutist, and would perform sequencing earlier. I’m also a realist.

4. Or really human genetics.

5. This requires calling more than 1000 times in the 1 hour window that appointments are open for a month. I don’t know how normal people can possibly do this. I had to write some code to automate this process and call 100s of times from several phone lines… this feels entirely unfair.

6. While I refer to my son as profoundly intellectually disabled. As yet I do not have a clear diagnosis he is referred to as “Intellectually Disabled with Autism” and classified as the highest level of disability (Aの1)…

By my untrained reading a diagnosis of intellectual disability with autism would not be appropriate under the diagnostic criteria outlined in the DSM-5 in my sons case:

“A diagnosis of autism spectrum disorder in an individual with intellectual disability is appropriate when social communication and interaction are significantly im­paired relative to the developmental level of the individual's nonverbal skills (e.g., fine motor skills, nonverbal problem solving). In contrast, intellectual disability is the appropri­ate diagnosis when there is no apparent discrepancy between the level of social-commu­nicative skills and other intellectual skills.”

While an accurate classification isn’t strictly necessary, it would be nice to have an accurate diagnosis to refer to, particularly when reading the literature.

7. Again, these things didn’t just happen. I needed to refer to the literature and point out that these were standard recommendations. In terms of metabolic testing it took significant effort to get anything more than a urine pH test.

8. And apologies for subjecting you to my family health issues. But at the end of the day this is one of the few tools at my disposal. We’ll be back to our regularly scheduled analysis of sequencing technology platforms shortly.