genetics

Posted on Autism

Clinical criteria for diagnosing autism inadequate for people with genetic conditions

DNA and Autism
DNA and Autism

People with certain genetic conditions are likely to have significant symptoms of autism, even if they do not meet all diagnostic criteria, a study concludes.

Researchers at Cardiff University say their findings show clinical services need to adapt so that people diagnosed with autism-linked genetic conditions are not denied access to vital support and interventions.

Published in The American Journal of Psychiatry, the international study analysed data from 547 people who had been diagnosed with one of four genetic conditions, also known as copy number variants (CNVs), associated with a high chance of autism – 22q11.2 deletion, 22q11.2 duplication, 16p11.2 deletion and 16p11.2 duplication.

CNVs happen when a small section of a person’s DNA is missing or duplicated. Certain CNVs have been linked to a range of health and developmental issues. They can be inherited but can also occur at random.

The results showed a high prevalence of autism in individuals with these four genetic conditions, ranging from 23% to 58%. The prevalence of autism in the general population is 1%. Using clinical cut-offs, the team also found 54% of people with these genetic conditions who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic symptoms. There was also considerable variability in symptoms of autism between those who had the same genetic condition.

Dr Samuel Chawner, based at Cardiff University’s MRC Centre for Neuropsychiatric Genetics and Genomics said: “Our study shows that an individualised approach is needed when assessing the needs of people with genetic conditions. Although many of those who were included in this study would not have met all of the criteria which define someone as having autism, more than half of those with these genetic conditions had significant symptoms associated with it – such as social and communication difficulties or repetitive behaviours.

“There is a danger that being too prescriptive with how autism is diagnosed will result in these individuals slipping through the net and being denied important services. Sadly, many families we have met through doing this research describe longstanding struggles in accessing autism support for their child. This is often due to a lack of integration between genetic testing services and autism diagnosis services.

“Low awareness of genetic conditions can also be a barrier. It is important that clinicians are aware of the risk of autism associated with certain genetic conditions in order to improve opportunities for early diagnosis and support.”

Data for the study was pooled from eight clinical research centres around the world, which had used the “Autism Diagnostic Interview – Revised (ADI-R)” and IQ tests on study participants.

The ADI-R is used internationally in research as well as in clinical settings for making autism diagnoses. It involves an interview with the parent or guardian and asks about the child’s developmental history across areas of social skills, communication skills and repetitive behaviours.

It is estimated that 15% of autistic people and 60% of people with developmental delay have a genetic condition.

Helen Hyde’s 16-year-old daughter, Hermione, was diagnosed with 22q.11.2 Deletion when she was four. Her genetic diagnosis first came to light after it was found she had a cleft palate, which affects her speech. She has Developmental Verbal Dyspraxia (DVD), which causes difficulties with how she processes and communicates language. As a consequence Mini attends a school for pupils with language disorders where she is fully supported in her education. She has also been diagnosed with comorbid anxiety.

Mini, as she’s known to her family, wasn’t formally diagnosed with autism until last year, even though researchers at Cardiff University and her school had previously flagged that she had autistic traits. The family have been involved in studies with Cardiff University’s Copy Number Variant research group for eight years.

“In many ways, the physical diagnosis of Mini’s cleft palate has been easier to deal with than the autism and mental health issues,” said Helen, also mum to Olivia, 19 and Edward, 23.

“People have less of an understanding of Mini’s autistic traits and it’s been much harder to get the right support for her.

“That’s why Cardiff University’s research in this area is so vital. It’s giving us the tools to be able to fight Mini’s corner so that she fulfils her potential.”

Mini said: “At first I did not know what 22q was but now I understand more. My main problem is my speech. Sometimes people don’t understand me and that can make me cross. Sometimes I find lessons difficult and I need a lot of help at school. I know they can learn lots of things from these studies and this will help people with 22q in the future.”

Tracy Elliot, Head of Research and Information at charity Cerebra, said: “We know many children and families frequently have problems in accessing autism support services or face very long delays. We welcome the findings of this research that indicate that individuals with different genetic conditions could benefit from the same autism support. This reinforces the case for improved support and should ease the path for parents and children with rare conditions.”

Posted on Autism

Human brain protein associated with autism confers abnormal behavior in fruit flies




 





A mutant gene that encodes a brain protein in a child with autism has been placed into the brains of fruit flies. Fruit flies hosting that gene produce the variant human brain protein and show abnormal behaviors of fear, repetitive activity and altered social interaction, reminiscent of autism impairments.

The genetic variant was found in the Simon Simplex Collection, which has collected genetic samples from 2,600 simplex families with autism spectrum disorder, or ASD. The brain protein is the dopamine transporter, or DAT, whose job is to pump the neurotransmitter dopamine back into nerve cells once the neurotransmitter has been released. The mutant protein is missing a single amino acid.

A study of this variant DAT — from its impaired molecular mechanism to its effect on fruit fly behavior — has been published in Proceedings of the National Academy of Sciences by co-corresponding authors Aurelio Galli, Ph.D., and Eric Gouaux, Ph.D.




Galli is professor in the Department of Surgery at the University of Alabama at Birmingham, and Gouaux is professor in the Vollum Institute at the Oregon Health & Science University and Howard Hughes Medical Institute.

Researchers found that fruit flies with the human variant DAT, or vDAT, are hyperactive. They had increased locomotor activity in both day and night, as compared with normal fruit flies. They also showed repetitive behavior — the vDAT fruit flies groomed themselves 23 percent of the time, versus 6 percent of the time for normal fruit flies. Repetitive behavior like self-grooming has been observed in animal models of neuropsychiatric disorders.

The vDAT fruit flies were also more fearful than normal fruit flies. In response to the sound of a predatory wasp, normal flies froze for about 150 milliseconds, and then they fled, as shown by a distinctive and rapid increase in average velocity that was captured by a 1,000-frame per second camera. In contrast, the vDAT fruit flies froze at the sound of the predator and showed little signs of fleeing during 600 milliseconds.

The vDAT fruit flies had impaired social interaction, as measured by changes in grouping. Many animal populations form temporary or permanent groups, such as flocks, schools or herds, that aid survival in the face of predators. Fleeing, in response to a threat, is an escape behavior where the flock size may compress or expand. The researchers found that normal fruit flies expanded their flock size in response to a threat — the sound of the predator wasp. The vDAT fruit flies, in contrast, compressed their flock size.

Besides the fruit fly behavior, the PNAS study is a comprehensive multidisciplinary approach that gets at some root causes of autism to a degree of detail that could make potential therapeutic treatments more realizable in the future.

Besides vDAT, the labs of Galli and Heinrich Matthies, Ph.D., assistant professor in the UAB Department of Surgery, have identified several other mutations in the human DAT gene that affect DAT function in individuals with ASD. For these people, disruption of dopamine transport appears to be a risk factor that promotes complications associated with ASD.

“The experimental paradigms we describe here,” Galli said, “provide a framework for molecular and behavioral analysis of novel DAT variants that are discovered by genetic analyses of individuals with ASD or related neuropsychiatric illness, as well as other disease-linked mutants that are emerging from precision medicine initiatives.”

Galli and Gouaux’s PNAS research went from human genetics to a basic animal model with simplified behavior, as detected by a new high-powered analysis. It investigated the underlying molecular mechanisms and basic biological functions with ever greater resolution, through studies at the cell level and all the way down to a bacterial system. Each added system was more fundamental with regard to biological complexity and phylogenetic level.

Details of vDAT structure and function Besides altered fly behavior caused by the mutant protein, the PNAS study probed the molecular structure and function of vDAT using mutation of a related transporter protein from a thermophilic bacterium as a model. Experiments included X-ray crystallography, spin resonance spectroscopy, molecular modeling, cell culture studies and electrophysiology studies of fruit fly brains expressing the mutant.

The researchers showed that vDAT cells have impaired dopamine transport and impaired DAT-mediated electrical currents. Also, expression of the human vDAT reduced dopamine uptake in the whole brain of fruit flies. These findings support the idea that human DAT dysfunction in ASD stems from specific and yet distinct mechanisms.

To probe the mechanism of impaired transporter function, researchers used the related bacterial transporter as a model. They removed the single amino acid from the related bacterial transporter that correlates with the single amino acid missing in vDAT. Like DAT, the bacterial transporter protein embeds across the cell membrane and has domains called the extracellular gate and the intracellular gate to receive and release the molecule being transported from outside the cell to inside.

Deletion of the single amino acid altered conformation of the bacterial protein and appeared to lock its extracellular gate, apparently through disrupted hydrogen bonds between amino acids of the protein that abnormally left the intracellular gate in a conformation called “half-open and inward facing.” Molecular dynamics simulation of vDAT showed similar conformational changes and altered hydrogen bonding.

 

 

Posted on ADHD, Autism

Sibling study bolsters genetic link between autism and ADHD

 




Children talking

Children talking




Children who have an older sibling with attention deficit hyperactivity disorder (ADHD) are at an increased risk of having autism, a new study suggests1. The reverse is also true.

Autism and ADHD share some features and often co-occur. Other studies have documented the increased risk in siblings for each of the conditions individually. But this is the first study to look at both conditions at once by homing in on the risk in younger siblings.

The results bolster the idea that there is a significant genetic overlap between the conditions.

The study’s findings are reliable because of its focus on later-born siblings, says lead researcher Meghan Miller, assistant professor of psychiatry and behavioral sciences at the University of California, Davis. Other studies may show an artificially low recurrence for these conditions because parents who have one diagnosed child sometimes choose not to have any more children — a phenomenon known as ‘stoppage.’




Read more here

Posted on Autism

Parents of autistic kids ‘have autistic traits’ as well says research




Autism families

Autism families




“Parents of children with autism are more likely to have autistic traits,” the Mail Online reports. The news comes from research comparing the families of children with autism spectrum disorder (ASD) with those that are unaffected.

Parents and children with ASD completed Social Responsiveness Scale (SRS) questionnaires designed to detect traits known to be associated with the condition.

The study found the risk of ASD increased by 85% when both parents had elevated SRS scores. Fathers’ elevated SRS scores significantly increased the risk of ASD in the child, but no association was found with mothers’ elevated scores.

The study also found elevated SRS scores for both parents significantly increased child SRS scores in children not reported to have ASD.




But this study has several limitations worth noting, particularly that it relied on what the mothers said to determine whether a child had ASD. This means that some children reported to have ASD may not actually have the condition.

It could simply be the case that naturally shy parents brought up a naturally shy child. Such reporting could be considered to be medicalising normal human behaviour.

Where did the story come from?

The study was carried out by researchers from the Harvard School of Public Health, the University of California, Washington University and other US institutions.

It was funded by grants from the US National Institutes of Health, Autism Speaks and the US Army Medical Research Material Command.

The study was published in the peer-reviewed medical journal JAMA Psychiatry.

There is a potential conflict of interest associated with the study, as the Social Responsiveness Scale used in the research was devised by one of the lead researchers involved in the study, Professor John Constantino, who also holds the copyright. Every time a copy of the scale is downloaded or posted, the professor receives a royalty. This conflict of interest is made clear in the study, however.

The Mail Online picked up the story and overall reported on the study appropriately. However, the website failed to mention that the ASD diagnosis was mainly determined by reports from the mothers involved. The news story implies that a diagnosis of ASD had been confirmed by a qualified medical professional.

What kind of research was this?

This was a nested case-control study carried out within a wider cohort study called the Nurses’ Health Study II.

A nested case-control study is a comparison of people who have a condition of interest (cases) with those who don’t (controls). The past histories and characteristics of the two groups are examined to see how they differ.

This type of study is often used to identify risk factors for uncommon or rare medical conditions. A nested case-control study is a special type of case-control study where cases and controls are selected from the same cohort of people (and are therefore “nested”).

In contrast to non-nested case-control studies, data is usually collected in advance (prospectively), which means researchers can be sure of when certain exposures or outcomes happened. This avoids the difficulties or biases of participants remembering (or misremembering) past events.

Also, as cases and controls are selected from the same cohort, this means they should be better matched than if researchers identified cases and controls separately.

What did the research involve?

Participants in this study were part of a wider cohort study called the Nurses’ Health Study II, which included 116,430 female nurses aged 25 to 42 years when they were recruited in 1989.

As part of the wider study, these women completed questionnaires posted to them every two years since recruitment. In 2005 they were asked whether any of their children had autism, Asperger’s syndrome or another condition on the autism spectrum.

Current thinking is that autism spectrum disorder (ASD) encompasses a range of conditions and associated symptoms. This can range from children with behavioural and learning difficulties (often referred to as autism) to children whose intelligence is unaffected but have problems with social interaction (known as Asperger’s syndrome).

The current study began in 2007. “Cases” were determined by mothers reporting ASD among their children. “Controls” were the children of women who did not have the condition. They were matched to the cases by birth year.

Of the original 3,756 women included in the study, the final analysis was performed on 1,649 participants. This was because some mothers failed to respond to follow-up questionnaires and some chose to no longer participate.

The researchers also excluded some participants, including those with missing information, mothers who failed to indicate they had a child with ASD on follow-up questionnaires, and any “controls” with ASD.

The main outcome of interest in the study was ASD assessed using the Social Responsiveness Scale (SRS). The SRS is a validated questionnaire used to assess behavioural and social communication traits.

It provides a single score that distinguishes individuals with ASD from individuals who do not have the condition and those with other psychiatric and developmental conditions.

A small proportion of cases (50) had maternal reports of ASD diagnosis validated using a diagnostic interview called the Autism Diagnostic Interview – Revised. SRS scores for children and fathers were completed by the nurses, whereas the mothers’ forms were completed by their spouse or a close relative.

The SRS scores were then examined by the researchers, who used statistical techniques to look for associations with the risk of ASD among the children. The children’s SRS scores were also examined in association with the SRS scores of their parents.

In their analysis, the researchers made adjustments for several confounders, including:

child sex

child year of birth

maternal and paternal age at birth

household income level

race

maternal pre-pregnancy obesity

maternal history of depression

divorce status

What were the basic results?

A total of 1,649 children were included in the final analyses: 256 children with ASD (cases) and 1,393 children who did not have the condition (controls).

The main findings from this study were:

risk of ASD was increased by 85% among children when both parents had elevated SRS scores (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.08 to 3.16)

fathers’ elevated SRS scores significantly increased the risk of ASD in the child (OR 1.94, 95% CI 1.38 to 2.71), but no association was found with mothers’ elevated SRS scores

elevated SRS scores for both parents significantly increased child SRS scores in the control children (an increase of 23 points on SRS)

How did the researchers interpret the results?

The researchers concluded they found evidence that parents of children with ASD had a greater social impairment than control parents, as measured by the Social Responsiveness Scale (SRS).

They also found that when both parents had elevated SRS scores, this increased the risk of ASD in the child.

They say that heritability of autism traits was supported through significant increases in child SRS scores according to elevated parent SRS scores among children without the condition.

Conclusion

Overall, this study provides limited evidence of an association between elevated Social Responsiveness Scores (SRS) among parents and the risk of autism spectrum disorder (ASD) in their children.

As the authors note, the study has several strengths, including that it adjusted for several potential confounders, such as maternal history of depression and maternal and paternal age at birth, and used cases and controls drawn from a larger study (the Nurses’ Health Study II).

However, the researchers do note this wider study is not ethnically or racially diverse, so its findings may not be generalisable to groups outside of those studied.

The wider study was also only carried out in nurses and this may also limit the generalisability of the study.

However, despite these strengths, there are several limitations worth noting.

Self-reporting

ASD was predominantly determined via maternal report, so it is likely that some of the “cases” actually did not have the condition and instead had a milder condition, no condition or another condition altogether.

The authors did attempt to account for this by validating a sub-group of cases using a diagnostic interview carried out by a trained health professional. However, this validation was only done for 50 “case” children.

Incomplete paternal information

The researchers say they also did not have complete information on the fathers of the children (for example, paternal history of depression was not accounted for as a confounder). This may have affected the results.

Reporting bias

There is also a possibility of reporting bias in that mothers completed forms for children and fathers, and fathers and close relatives completed forms for mothers.

As ASD is thought to be associated with genetics (although environmental factors are also thought to be involved), the hypothesis that parental traits may contribute towards a child’s condition is plausible.

But it is also possible that some children grow up to have a similar personality to their parents. While ASD is a recognised neurological condition, being introverted and shy is just part of the wider range of human personalities. We should always be vigilant that we don’t start trying to fix problems that do not actually exist*.
*

Posted on Autism

PAC1R mutation may be linked to severity of social deficits in autism

 

This is Joshua G. Corbin, Ph.D., interim director of the Center for Neuroscience Research at Children’s National Health System and the study’s co-senior author. CREDIT Children’s National Health System

A mutation of the gene PAC1R may be linked to the severity of social deficits experienced by kids with autism spectrum disorder (ASD), finds a study from a multi-institutional research team led by Children’s faculty. If the pilot findings are corroborated in larger, multi-center studies, the research published online Dec. 17, 2018, in Autism Research represents the first step toward identifying a potential novel biomarker to guide interventions and better predict outcomes for children with autism.

As many as 1 in 40 children are affected by ASD. Symptoms of the disorder – such as not making eye contact, not responding to one’s name when called, an inability to follow a conversation of more than one speaker or incessantly repeating certain words or phrases – usually crop up by the time a child turns 3.

The developmental disorder is believed to be linked, in part, to disrupted circuitry within the amygdala, a brain structure integral for processing social-emotional information. This study reveals that PAC1R is expressed during key periods of brain development when the amygdala – an almond-shaped cluster of neurons – develops and matures. A properly functioning amygdala, along with brain structures like the prefrontal cortex and cerebellum, are crucial to neurotypical social-emotional processing.

“Our study suggests that an individual with autism who is carrying a mutation in PAC1R may have a greater chance of more severe social problems and disrupted functional brain connectivity with the amygdala,” says Joshua G. Corbin, Ph.D., interim director of the Center for Neuroscience Research at Children’s National Health System and the study’s co-senior author. “Our study is one important step along the pathway to developing new biomarkers for autism spectrum disorder and, hopefully, predicting patients’ outcomes.”

The research team’s insights came through investigating multiple lines of evidence:

They looked at gene expression in the brains of an experimental model at days 13.5 and 18.5 of fetal development and day 7 of life, dates that correspond with early, mid and late amygdala development. They confirmed that Pac1r is expressed in the experimental model at a critical time frame for brain development that coincides with the timing for altered brain trajectories with ASD.

They looked at gene expression in the human brain by mining publicly available genome-wide transcriptome data, plotting median PAC1R expression values for key brain regions. They found high levels of PAC1R expression at multiple ages with higher PAC1R expression in male brains during the fetal period and higher PAC1R expression in female brains during childhood and early adulthood.

One hundred twenty-nine patients with ASD aged 6 to 14 were recruited for behavioral assessment. Of the 48 patients who also participated in neuroimaging, 20 were able to stay awake for five minutes without too much movement as the resting state functional magnetic resonance images were captured. Children who were carriers of the high-risk genotype had higher resting-state connectivity between the amygdala and right posterior temporal gyrus. Connectivity alterations in a region of the brain involved in processing visual motion may influence how kids with ASD perceive socially meaningful information, the authors write.

Each child also submitted a saliva sample for DNA genotyping. Previously published research finds that a G to C single nucleotide polymorphism, a single swap in the nucleotides that make up DNA, in PAC1R is associated with higher risk for post traumatic stress disorder in girls. In this behavioral assessment, the research team found children with autism who carried the homozygous CC genotype had higher scores as measured through a validated tool, meaning they had greater social deficits than kids with the heterozygous genotype.

All told, the project is the fruit of six years of painstaking research and data collection, say the researchers. That includes banking patients’ saliva samples collected during clinical visits for future retrospective analyses to determine which genetic mutations were correlated with behavioral and functional brain deficits, Corbin adds.

“Lauren Kenworthy, who directs our Center for Autism Spectrum Disorders, and I have been talking over the years about how we could bring our programs together. We homed in on this project to look at about a dozen genes to assess correlations and brought in experts from genetics and genomics at Children’s National to sequence genes of interest,” he adds. “Linking the bench to bedside is especially difficult in neuroscience. It takes a huge amount of effort and dozens of discussions, and it’s very rare. It’s an exemplar of what we strive for.”