Scientists Closer to Predicting DiGeorge Syndrome Prognosis

Liam Davenport

August 06, 2015

UPDATED August 10, 2015 // Children with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome, have different patterns of gene expression, depending on whether they develop autism or psychosis, new research shows.

The study, which used a novel technique for identifying patterns of gene expression, also found there was an overlap between the differentially expressed genes and those previously identified in studies of individuals with idiopathic psychosis and autism.

"Collectively, these findings provide a first step toward understanding the functional gene networks disrupted by the 22q11.2 deletion, which may relate to variable phenotypic expression of the disorder," the investigators write.

"Future investigations in human in vitro cellular models and in animal models of 22q11.2 mutations are necessary to link the affected genetic pathways to molecular mechanisms, which may be targeted for biologically informed interventions."

The study was published online July 22 in PLOS ONE.

High Risk for Multiple Psychiatric Disorders

"One of the really puzzling things about this disorder, and also various other copy number variants, is that they are associated with a really high risk of multiple psychiatric disorders," said Carrie Bearden, PhD, the study's senior author and professor of psychiatry and psychology at the University of California, Los Angeles (UCLA).

Noting that the factors related to autism and psychosis are not well understood, she told Medscape Medical News: "What we are interested in is looking not just at within that particular segment of the genome but genome-wide."

"How does this affect gene expression?... Is the expression of genes different as a function of having this deletion, [and] does that relate to these different outcomes in terms of different psychiatric disorders?"

To identify genes and pathways related to specific phenotypes in 22q11.2DS, the researchers studied 46 patients with a molecularly confirmed diagnosis of a 22q11.2 deletion, 24 unrelated healthy individuals, who served as controls, and 42 family members, who served as controls. The average ages of these persons were 17.3 years, 15.4 years, and 41.7 years, respectively.

All participants completed the Computerized Diagnostic Interview Schedule for Children and/or the Structured Clinical Interview for DSM-IV Axis I Disorders; patients were also administered the SIPS/Scale of Prodromal Syndromes. The Autism Diagnostic Observation Schedule was administered to the children, and Autism Diagnostic Interview–Revised was administered to their parent/primary caretaker.

RNA was extracted from whole blood samples, and whole-genome transcription profiling was performed. To look for patterns of related genes, the team also performed weighted gene coexpression network analysis, a novel technique developed at UCLA by geneticist Steve Horvath, PhD, ScD.

The results showed that there was substantial differential gene expression between patients and control persons.

Among 22q11.2DS patients with psychosis, 237 genes showed a different pattern of expression compared with 22q11.2DS patients without psychosis. The majority of the genes were related to gene expression.

Comparing the findings with a sample of Dutch patients with schizophrenia but without 22q11.2DS, they found an overlap of seven genes from the 237 previously identified, all of which are involved in fetal brain development.

There were 86 genes that were differentially expressed in 22q11.2DS patients with autism compared with those without autism, which were primarily related to immunologic processes and functions. A comparison with published data indicated that four of the 86 genes had been previously associated with idiopathic autism spectrum disorder.

Discussing the potential applications of the findings, Dr Bearden said that the ultimate goal would be to use a blood biomarker to predict diagnostic outcome, although she conceded that it "would be really premature to say that we could do that now."

Another question is how relevant the results are to what is happening in the brain. She noted that although they found a significant overlap with genes that are expressed in the brain, more research is required.

Dr Bearden and colleagues are therefore conducting a study in collaboration with Stanford University with induced pluripotent stem cells taken from patients with 22q11.2DS.

"With that, we can differentiate those stem cells into neurons and really look at what's happening and see how this actually affects neurons," she said.

Another avenue of investigation for the team is to apply the same methodology to, for example, patients with a duplication in the same region of the genome.

"We're looking right now, basically, at how this mirror image loss vs gain of function of this chunk of DNA differently affects behavior," said Dr Bearden.

It may also offer insights into individuals with missing genes on chromosomes 15 and 16. These individuals have high rates of autism, psychosis, intellectual disability, and epilepsy, "not necessarily in the same people but with apparently the same genetic etiology, and so I think that this is a way to try to disentangle those things," she concluded.

A Step in the Right Direction

Commenting on the findings for Medscape Medical News, Vandana Shashi, MD, professor of pediatrics in the Department of Pediatrics-Medical Genetics, Duke University School of Medicine, Durham, North Carolina, said that although the results are "very intriguing, they are preliminary, and they need to be replicated with larger sample sizes across different developmental stages."

Although noting that the researchers used a good neuropsychological battery, she said that there are some methodologic limitations to the study.

"Overall, it was a reasonable sample size, but for looking at specific phenotypes within that, it's small," Dr Shashi continued. "So I think the conclusions you come to have to be cautiously interpreted."

Referring to the fact that the expression studies were conducted in blood samples, she added: "I understand the limitations of getting brain tissue in these individuals, but expression in blood doesn't always mean that you'll have the same expression patterns in the brain, which is the organ of interest for the psychological and psychiatric manifestations."

"I think with those constraints, it's a very interesting paper. I would interpret it as a preliminary report that needs to be further substantiated."

As to whether the findings could eventually point toward a biomarker for determining the prognosis of an individual with 22q11.2DS, Dr Shashi was equally cautious.

"Unless we have further reports and larger sample sizes that this is likely to lead to a biomarker, I would reserve judgement on that at this time."

However, she concluded: "It's certainly a step in the right direction."

Dr Shashi's comments were echoed by Therese van Amelsvoort, MD, PhD, from the Department of Psychiatry and Neuropsychology, Maastricht University, the Netherlands.

"The article is a very interesting, and its method, gene expression profiling within this population, is something that has hardly been done," she told Medscape Medical News.

"There was one other study that was done before from my own group, but it was a much smaller sample, and we looked at the differences between psychotic and nonpsychotic people."

"They have taken it a step further ― to study a larger sample, first of all, and also to look at different patterns between those that are psychotic and nonpsychotic and those that are autistic and nonautistic," she said

Nevertheless, Dr van Amelsvoort noted: "You still have to take into consideration that it's a relatively small sample, and also particularly for the psychotic people, it's a young sample, and a lot of people haven't really passed the risk age of developing a psychosis."

"So to make bold statements about psychosis in that young a population, you have to be cautious. Nevertheless, its methodology is very brilliant, and the patterns are interesting."

Dr van Amelsvoort also pointed out that the lack of data on gene expression in the brain limits the clinical utility of the findings, particularly because it is not possible to obtain in vivo brain samples, and there are no postmortem data.

"The information we get about this gene expression is on the basis of blood, and that doesn't mean it's the same in brain.... We can make assumptions, but we can't check that because we cannot look in the brain," she said.

"There's still a long way to go, and the authors know that," she added.

The authors received funding from a variety of sources, which are listed in the original article.

PLoS One. Published online July 22, 2015. Full text


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