15q11.2 microdeletion, developmental delay and congenital heart disease

"Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease."

So it was written in the paper from Vanlerberghe and colleagues [1] following their analysis of 52 "unrelated patients" diagnosed with 15q11.2 microdeletion, a 'novel' microdeletion syndrome according to other research [2].

Your REAL problem's the monkey.

Autism spectrum disorder (ASD) is mentioned in the Vanlerberghe paper as per the suggestion that "63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder" and hence why this paper is fodder for this blog. Quite ESSENCE-like if you want my honest opinion.

Actually, I do have a few other reasons for briefly discussing this paper, bearing in mind my considerable lack of knowledge and experience when it comes to all-things genetics. So, quite recently I talked about 15q Duplication Syndrome (Dup15q) (see here) and how the gut and gastrointestinal (GI) symptoms have been a focus not so long ago. I know that Dup15q and 15q11.2 microdeletion are not the same thing - one is about gains and the other about losses of genetic material (I think!) - but they are talking about the same chromosome, and that chromosome has been linked to quite a few conditions (see here). I wondered whether anyone had investigated GI issues in cases of 15q11.2 microdeletion? Answer: sort of [3] with perhaps lots more research to do.

The other reason I was drawn to the Vanlerberghe paper was the suggestion of "associated congenital heart disease in 17.3%" of their participant group. Congenital heart disease (CHD) covers quite a bit of diagnostic ground and again, I don't profess to be an expert in this area. That being said, I'll draw your attention to a post written not-so-long-ago discussing the paper from Hilda Razzaghi and colleagues [4] (see here) which concluded that: "Children aged 2-17 with CHD were more likely than those without CHD to have had a diagnosis of autism spectrum disorder (crude OR, 4.6; 95% CI, 1.9-11.0) or intellectual disability (crude OR, 9.1; 95% CI, 5.4-15.4)." It strikes me that 15q11.2 microdeletion might have something further to contribute when it comes to any future research talking about CHD and autism (or autism+). I'm not saying that the microdeletion will universally fill in the blanks but it might play a possible role.

And now for some opera... from Carmen - Habanera.

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[1] Vanlerberghe C. et al. 15q11.2 Microdeletion (BP1-BP2) and Developmental delay, Behaviour issues, Epilepsy and Congenital heart disease: a series of 52 patients. Eur J Med Genet. 2015 Jan 14. pii: S1769-7212(15)00006-3.

[2] Doornbos M. et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader–Willi critical region, possibly associated with behavioural disturbances. European Journal of Medical Genetics. 2009; 52: 108-115.

[3] Wong D. et al. Expanding the BP1-BP2 15q11.2 Microdeletion Phenotype: Tracheoesophageal Fistula and Congenital Cataracts. Case Reports in Genetics. 2013. 801094.

[4] Razzaghi H. et al. Long-term outcomes in children with congenital heart disease: national health interview survey. J Pediatr. 2015 Jan;166(1):119-124.e1.

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Vanlerberghe C, Petit F, Malan V, Vincent-Delorme C, Bouquillon S, Boute O, Holder-Espinasse M, Delobel B, Duban B, Vallee L, Cuisset JM, Lemaitre MP, Vantyghem MC, Pigeyre M, Lanco-Dosen S, Plessis G, Gerard M, Decamp M, Mathieu M, Morin G, Jedraszak G, Bilan F, Gilbert-Dussardier B, Fauvert D, Roume J, Cormier-Daire V, Caumes R, Puechberty J, Genevieve D, Sarda P, Pinson L, Blanchet P, Lemeur N, Sheth F, Manouvrier-Hanu S, & Andrieux J (2015). 15q11.2 Microdeletion (BP1-BP2) and Developmental delay, Behaviour issues, Epilepsy and Congenital heart disease: a series of 52 patients. European journal of medical genetics PMID: 25596525

The gut and 15q Duplication Syndrome

"The results indicate that GI [gastrointestinal] symptoms are common in Dup15q syndrome and may have an atypical presentation."

Let's just say I'm Frankenstein's monster.
And I'm looking for my creator.

That was the conclusion reached in the paper by Elias Shaaya and colleagues [1] following a review of medical records for a small-ish group of participants diagnosed with chromosome 15q duplication syndrome (dup15q syndrome), a genetic condition "involving copy number gains of the maternal chromosome 15q11.2-q13 region." Dup15q syndrome can manifest in a variety of ways including the presence of seizure disorders, poor muscle tone (hypotonia), issues with growth and neurodevelopmental issues.

Authors reported functional GI symptoms to be present in over three-quarters of their cohort, slightly varying in frequency depending on the nature of duplication (isodicentric vs. interstitial duplication) recorded. "The most commonly reported symptoms were gastroesophageal reflux (56.7%) and constipation (60%), with 30% of subjects reporting both" and: "Behaviors such as irritability and aggressiveness improved with treatment of GI symptoms in several subjects."

Why am I talking about dup15q syndrome on a blog that is supposed to be concentrating on autism research?

Well, three reasons: first, dup15q syndrome shares some overlap with the presentation of autism/autistic traits in the more general sense as per other commentaries on the topic (see here and see here). Second, the Shaaya study represents a second research foray into GI issues associated with genetic conditions with autism mentioned as part of some presentation, as per the discussions last year (2014) on GI issues appearing alongside 22q11.2 deletion syndrome (see here). Finally, dup15q has been mentioned on this blog before with the curious findings reported by Mitchell and colleagues [2] who implied that: "specific POPs [persistent organic pollutants] may predispose to genetic copy number variation of 15q11-q13." That last reason ties into my interest in how genes and environment [variably] intersect when it comes to health and wellbeing particularly associated with behaviourally-defined diagnoses.

The comment about how treatment of GI symptoms seemed to tie into a reduction in certain 'challenging behaviours' in cases of dup15q syndrome is also worthy of further promotion. As per my review of autism research in 2014, functional GI issues associated with quite a few cases of autism was an ascendancy topic of investigation, further compounded by papers such as the one from Zainab Ridha and colleagues [3] (see here) on autism being one of a number of "useful predictors of STC and FFR [slow transit constipation and functional fecal retention] in children." Alongside other research suggesting that issues such as anxiety and sensory 'over-responsivity' might also tie into the presentation of GI problems in autism (see here), one might see how management/treatment of bowel issues may very well impact on some behaviours. No-one likes to walk around with chronic constipation.

I know the Shaaya paper was based on a relatively small number of participants, so it is perhaps implied that further studies are needed to see how generalised GI issues might be in relation to dup15q syndrome. As per that Giardino study [4] on GI involvement in 22q11.2 deletion syndrome (del22), one wonders whether looking at things like "antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers" might also be a useful next step, alongside horror of horrors, the presence of any "abnormal intestinal permeability"?

Prefab Sprout - The King of Rock 'N' Roll to close.

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[1] Shaaya EA. et al. Gastrointestinal Problems in 15q Duplication Syndrome. European Journal of Medical Genetics. 2015. January 5.

[2] Mitchell MM. et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environ Mol Mutagen. 2012 Oct;53(8):589-98.

[3] Ridha Z. et al. Predictors of slow colonic transit in children. Pediatr Surg Int. 2014 Dec 31.

[4] Giardino G. et al. Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scand J Gastroenterol. 2014 Mar;49(3):274-9.

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Shaaya, E., Pollack, S., Boronat, S., Davis-Cooper, S., Zella, G., & Thibert, R. (2015). Gastrointestinal Problems in 15q Duplication Syndrome European Journal of Medical Genetics DOI: 10.1016/j.ejmg.2014.12.012