autism and genetics

Posted on Autism

New Genetic Discovery Sheds Light on Autism

DNA and autism
DNA and autism

Researchers have uncovered a new genetic link to autism, offering fresh insights into why the condition is more common in males. The breakthrough, detailed in The American Journal of Human Genetics, identifies variants in the DDX53 gene, located on the X chromosome, as key contributors to autism. This finding provides a deeper understanding of the biological mechanisms behind autism and could improve diagnosis and treatment.

A Genetic Clue to Male Prevalence

Autism affects more males than females, and this new study helps explain why. Researchers at The Hospital for Sick Children (SickKids) in Canada, in collaboration with the Istituto Giannina Gaslini in Italy, analyzed families with autistic members. They discovered that specific variants in the DDX53 gene were maternally inherited in individuals with autism—most of whom were male.

“By pinpointing DDX53 as a key player, particularly in males, we can better understand the biological mechanisms at play and improve diagnostic accuracy for individuals and their families,” says Dr. Stephen Scherer, Senior Scientist at SickKids and a lead researcher in the study.

The DDX53 gene is involved in brain development and function but had not previously been linked to autism. Another gene nearby, PTCHD1-AS, also showed potential involvement. For example, one boy and his mother, both autistic with minimal support needs, had a genetic deletion that included parts of DDX53 and PTCHD1-AS.

International Collaboration Strengthens Findings

This discovery resulted from a global effort involving institutions in Canada, Italy, and the United States. Using databases like Autism Speaks’ MSSNG and the Simons Foundation Autism Research Initiative, researchers identified 26 more individuals with similar DDX53 variants, strengthening the evidence for its role in autism.

Lead author Dr. Marcello Scala, from the Istituto Giannina Gaslini, highlighted the importance of this discovery:
“This gene has long eluded us. Linking DDX53 to autism not only advances clinical genetic testing but also opens up new areas of research into the behavioural traits associated with autism.”

The Bigger Picture: The Role of the X Chromosome

In a related study published alongside this one, Scherer and his team identified 59 genetic variants on the X chromosome-linked to autism. These included DMD, HDAC8, and FGF13, among others. Importantly, some of these genes, like FGF13, show sex-specific differences, further emphasizing the role of the X chromosome in autism’s male predominance.

“These findings provide new insights into the biology of the X chromosome in autism,” says Scherer. “They suggest that certain genes, such as DDX53 and FGF13, should be explored further.”

Rethinking Autism Research

Interestingly, the study points out a challenge in current research models: DDX53 does not have an equivalent gene in commonly used lab animals like mice. This means researchers must rethink how they study autism in the lab.

“Insights from this study could significantly influence the design and interpretation of autism research, particularly in developing new models,” Scherer adds.

Hope for Families

These findings could pave the way for more precise diagnostic tools and treatments for autism, bringing hope to millions of families worldwide. Scherer emphasizes the importance of these discoveries:
“Both studies provide even more evidence that complex neurobehavioral conditions like autism can sometimes have simple biological underpinnings.”

By identifying key genetic factors like DDX53, researchers are not only unraveling the mysteries of autism but also laying the groundwork for more effective support for autistic individuals and their families.

Posted on Autism

Key breakthrough in autism research : pivotal role of condensates demonstrated

IRB Barcelona team

A study by IRB Barcelona unveils how the lack of a fraction of the CPEB4 protein causes a decrease in the expression of genes crucial for neuronal development. Credit IRB Barcelona

Autism is a neurodevelopmental disorder characterized by challenges in communication and social behaviour. About 20% of cases are linked to a specific genetic mutation, while the origin of the remaining 80%, referred to as idiopathic autism, remains unknown.

A team of scientists led by Drs. Raúl Méndez and Xavier Salvatella at the Institute for Research in Biomedicine (IRB Barcelona), has discovered a molecular mechanism that explains why certain alterations in the neuronal protein CPEB4 are linked to idiopathic autism.

The study builds upon previous research published in 2018, which identified CPEB4 as an essential protein in regulating neuronal proteins associated with autism. In that earlier study, researchers found that individuals with autism were missing a specific neuronal microexon, a tiny segment of genetic material vital for proper protein function in neurons. The new findings published in the journal Nature highlight the significance of this tiny fragment in neuronal activity, as it allows CPEB4 to form and disassemble protein condensates effectively.

“This study offers new insights into how minor modifications in proteins that regulate gene expression can significantly influence neuronal development. This discovery opens up new avenues for exploring future therapies,” explains Dr Méndez, an ICREA researcher and head of the Translational Control of Cell Cycle and Differentiation laboratory at IRB Barcelona.

Molecular condensates and gene regulation

The region of the CPEB4 protein that holds the segment lacks a well-defined three-dimensional structure. Proteins with disordered regions can form condensates, like tiny droplets within the cell where molecules, such as messenger RNAs (mRNAs) that code for other proteins involved in neuronal function, are stored in a silenced state. These condensates can assemble and disassemble in response to cellular signals, enabling dynamic regulation of gene expression.

“In this study, we have discovered that this neuronal microexon is essential for maintaining the stability and dynamics of the condensates formed by CPEB4 in neurons. Without the microexon, these condensates become less dynamic and can aggregate into solid forms that do not function properly,” says Dr Salvatella, an ICREA researcher and head of the Laboratory of Molecular Biophysics at IRB Barcelona.

This lack of dynamism prevents the mRNAs stored in these condensates from being released when neurons are stimulated, leading to decreased production of proteins essential for neuronal development and function. Among these mRNA molecules are many genes previously linked to autism.

Implications for neuronal development

Proper regulation of these genes is essential during brain development. If these CPEB4 condensates do not function correctly due to the absence of the neuronal micro exon, disruptions of neuronal development can occur, manifesting as symptoms of autism. The described mechanism also helps to explain the complexity and heterogeneous nature of idiopathic autism, as this spectrum includes multiple manifestations and varying degrees of severity.

“Our results suggest that even small decreases in the percentage of microexon inclusion can have significant effects. This would explain why some individuals without a gene mutation develop idiopathic autism,” explain Drs: Carla Garcia-Cabau and Anna Bartomeu, IRB Barcelona researchers and first authors of the study.

The concept proposed in this study of gene regulation in neurons through the formation of condensates may also have implications for ageing. Over time, these condensates lose their plasticity, meaning their capacity to assemble and disassemble, which could impair proper neuronal function and promote the development of neurodegenerative diseases.

Possible avenues for future therapies

One of the study’s promising findings is that micro exon 4 appears to work “in trans,” which means that it might be possible to introduce this small sequence of amino acids into cells to partially restore CPEB4 function and potentially reverse the symptoms.

“Although we’re still in exploratory stages, this discovery is promising and points to a potential therapeutic approach that could restore CPEB4 function,” says Dr. Méndez. The researchers emphasise that this finding still requires extensive experimental testing, such as studies in animal models and overcoming multiple technical barriers.

Posted on Autism

The study reveals brain mechanisms involved in genetically based autism; findings may lead to effective treatment

PhD student Inbar Fischer

PhD student Inbar Fischer Credit Tel Aviv University

A groundbreaking study from Tel Aviv University enhances our understanding of the biological mechanisms behind genetically based autism. It mainly focuses on mutations in the SHANK3 gene, which are responsible for nearly one million autism cases worldwide. Based on these findings, the research team applied a genetic treatment that improved the functioning of cells affected by the mutation, paving the way for future therapies for SHANK3-related autism.

The study was led by the lab of Prof. Boaz Barak and PhD student Inbar Fischer from the Sagol School of Neuroscience and the School of Psychological Sciences at Tel Aviv University.

Prof. Barak: “Autism is a common neurodevelopmental disorder affecting 1-2% of the global population, with one in every 36 boys in the U.S. diagnosed. Its causes include environmental, genetic, and social factors, such as advancing parental age at conception.  In my lab, we focus on the genetic causes of autism, particularly mutations in the SHANK3 gene. This gene is vital for the protein that binds receptors in neurons, essential for receiving chemical signals that enable neuron communication. Damage to SHANK3 can disrupt this communication, impairing brain development and function.  Our study aims to explore previously unknown mechanisms through which SHANK3 mutations affect brain development, leading to autism.”

Specifically, the research team focused on two components in the brain that have not yet been studied extensively in this context: non-neuronal brain cells (glia) called oligodendrocytes and the myelin they produce. Myelin tissue is a fatty layer that insulates nerve fibres (axons), similar to the insulating layer that coats electrical cables. When the myelin is faulty, the electrical signals transmitted through the axons may leak, disrupting the message transmission between brain regions and impairing brain function.

The team employed a genetically engineered mouse model for autism, introducing a mutation in the Shank3 gene that mirrors the mutation found in humans with this form of autism. Inbar Fischer: “Through this model, we found that the mutation causes a dual impairment in the brain’s development and proper function: first, in oligodendrocytes, as in neurons, the SHANK3 protein is essential for the binding and functioning of receptors that receive chemical signals (neurotransmitters and others) from neighbouring cells. This means that the defective protein associated with autism disrupts message transmission to these vital support cells. Secondly, when the function and development of oligodendrocytes is impaired, their myelin production is also disrupted. The faulty myelin does not properly insulate the neuron’s axons, thereby reducing the efficiency of electrical signal transmission between brain cells and the synchronization of electrical activity between different brain parts. In our model, we found myelin impairment in multiple brain areas and observed that the animals’ behaviour was adversely affected.”

The researchers then sought a method for fixing the damage caused by the mutation, hoping to develop a treatment for humans ultimately. Inbar Fischer: “We obtained oligodendrocytes from the brain of a mouse with a Shank3 mutation and inserted DNA segments containing the normal human SHANK3 sequence. Our goal was to allow the normal gene to encode a functional and normal protein, which would perform its essential role in the cell by replacing the defective protein. To our delight, following treatment, the cells expressed the normal SHANK3 protein, enabling the construction of a functional protein substrate to bind the receptors that receive electrical signals. In other words, the genetic treatment we had developed repaired the oligodendrocytes’ communication sites, essential for the cells’ proper development and function as myelin producers.”

To validate findings from the mouse model, the research team generated induced pluripotent stem cells from the skin cells of a girl with autism caused by a SHANK3 gene mutation identical to that in the mice. From these stem cells, they derived human oligodendrocytes with the same genetic profile. These oligodendrocytes displayed impairments similar to those observed in their mouse counterparts.

Prof. Barak concludes: “In our study, we discovered two new brain mechanisms involved in genetically induced autism: damage to oligodendrocytes and, consequently, damage to the myelin they produce. These findings have important implications – both clinical and scientific.  Scientifically, we learned that defective myelin played a significant role in autism and identified the mechanism causing the damage to myelin. Additionally, we revealed a new role for the SHANK3 protein: building and maintaining a functional binding substrate for receptors critical for message reception in oligodendrocytes (not just in neurons). We discovered that contrary to the prevailing view, these cells play essential roles in their own right, far beyond the support they provide for neurons — often seen as the leading players in the brain. In the clinical sphere, we validated a gene therapy approach that led to significantly improved development and function of oligodendrocytes derived from the brains of mice modelling autism. This finding offers hope for developing genetic treatment for humans, which could enhance the myelin production process in the brain. Furthermore, recognizing the significance of myelin impairment in autism—whether linked to the SHANK3 gene or not—opens new pathways for understanding the brain mechanisms underlying autism and paves the way for future treatment development.

Posted on Autism, Genetics

New genetic clues have been discovered in the largest study of families with multiple children impacted by autism.

UCLA Health researchers have published the largest-ever study of families with at least two children with autism, uncovering new risk genes and providing new insights into how genetics influence the development of autism.

The new study, published on July 28 in the Proceedings of the National Academy of Sciences, also provides genetic evidence that language delay and dysfunction should be reconsidered as a core component of autism.

The majority of genetic studies on autism have concentrated on families with a single affected child, often excluding families with multiple affected children. Consequently, very few studies have explored the impact of rare inherited genetic variations or their interaction with the collective effect of multiple common genetic variations that contribute to the risk of developing autism.

“Study design is critical, and not enough attention has been paid to studying families with more than one affected child,” said lead study author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology, and Psychiatry at UCLA.

“Autism is highly heritable. It is estimated that at least 50% of the genetic risk is attributed to common genetic variations, while another 15-20% is due to spontaneous mutations or predictable inheritance patterns. The remaining genetic risk is still not completely understood.”

For this study, researchers conducted whole-genome sequencing on 4,551 individuals from 1,004 families, including 1,836 children with autism and 418 without.

The researchers found seven potential genes linked to autism: PLEKHA8, PRR25, FBXL13, VPS54, SLFN5, SNCAIP, and TGM1. This is notable because previous studies needed larger cohorts to find a similar number of new risk genes. Most of the new genes were supported by rare inherited DNA variations passed from parents to children with autism.

The researchers also looked into polygenic risk, which involves a combination of commonly found genetic variations that can increase the likelihood of developing autism. They discovered that children who inherit rare mutations from unaffected parents, combined with polygenic risk, are more likely to have autism. This helps to explain why parents who have a single rare mutation may not display signs of autism, even if their children do. It also supports the liability threshold model, a concept in behavioral genetics that suggests there is an additive effect of genes influencing the probability of developing a certain trait.

Children who experienced language delay were more likely to inherit a polygenic score linked to autism, compared to children without language delays. This association was specific to autism and was not observed for other traits such as educational attainment, schizophrenia, or bipolar disorder. This suggests a connection between the genetic predisposition for autism and language delay.

The most recent edition of the professional guidebook used by mental health providers to diagnose disorders, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), does not consider language delay a core symptom of autism. This is due to the variability in language ability among people with autism.

“This association of general risk for autism that was strongest in those with language delay suggests that language is actually a core component of autism. This finding needs to be replicated in larger cohorts, especially those recruited more recently under DSM-5,” Geschwind said.

Posted on Autism

Autistic siblings share more of dad’s genome, not mum’s

Parental genome sharing among siblings with autism

CAPTION

For decades, Cold Spring Harbor Laboratory scientists and collaborators have invested millions of dollars into deciphering the genetic causes of autism Cold Spring Harbor Laboratory

Cold Spring Harbor Laboratory (CSHL) researchers have flipped the script on autism ) genetics.

Scientists long thought that siblings born with autism share more of their mother’s genome than their father’s. But CSHL Associate Professor Ivan Iossifov and Professor Michael Wigler have now shown that, in many cases, it’s dad who might be playing a bigger genetic role.

Autism spectrum disorders cover a range of neurological and developmental conditions. They can affect how a person communicates, socializes, learns, and behaves. Autism may also manifest as repetitive behaviors or restricted interests. In the United States, it affects around one in 36 children. 

“There are children diagnosed with autism who are high functioning,” Iossifov says. “They have a completely productive life, although they have some minor troubles in social interactions, as most of us do. But also, there are children diagnosed with autism who never learn to speak, and they have definitely a difficult life.”

Over the last two decades, CSHL scientists have led a multimillion-dollar effort to uncover the genetic origins of autism. They discovered thousands of genes that, when damaged, may cause a child to be born with autism. But their work was not able to account for all cases of autism. So Iossifov and Wigler set out to find the missing sources.

The duo analyzed the genomes of over 6,000 volunteer families. They found that in families that have two or more children with autism, the siblings shared more of their father’s genome. Meanwhile, in families where only one sibling had autism , the children shared less of their father’s genome. While the discovery reveals a new potential source of autism, it also poses a provocative question. Could other disorders play by the same genetic rules?

No one is sure how dad’s genome makes its mark on children with autism. But Iossifov has a couple interesting ideas. He thinks some fathers may carry protective mutations that fail to get passed on. Or fathers may pass down mutations that trigger the mother’s immune system to attack the developing embryo. Both theories offer hope for parents of children with autism .

“Our future research is exciting,” Iossifov says. “If one of those theories or two of them prove to be true, then it opens different treatment strategies, which can, in the future, affect quite a lot of families.”

In addition, this research offers helpful tools for educators and therapists. It may allow for earlier diagnoses and a better overall understanding of autism.