March 1, 2024

Prediction of neurodevelopmental diseases in children based on parental characteristics

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Neurodevelopmental and psychiatric disorders, and the genes that can lead to them, vary across a population (on the left, brighter red colors represent more severe symptoms, asterisks represent individuals with genetic variants that are at high risk of developing such disorders). A new study that looked at 97,000 families observed assortative mating for these traits, with good correlation between parental traits (middle). The researchers showed that assessing both parents for these traits, in addition to high-risk genetic variants, improved their ability to predict the prevalence and, potentially, severity of diseases in children (right). Credit: Girirajan Laboratory, Penn State

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Neurodevelopmental and psychiatric disorders, and the genes that can lead to them, vary across a population (on the left, brighter red colors represent more severe symptoms, asterisks represent individuals with genetic variants that are at high risk of developing such disorders). A new study that looked at 97,000 families observed assortative mating for these traits, with good correlation between parental traits (middle). The researchers showed that assessing both parents for these traits, in addition to high-risk genetic variants, improved their ability to predict the prevalence and, potentially, severity of diseases in children (right). Credit: Girirajan Laboratory, Penn State

Predicting the trajectory of neurodevelopmental and psychiatric disorders, such as autism or schizophrenia, is difficult because they can be influenced by many different genetic and environmental factors.

A new study, led by researchers at Penn State, demonstrates that assessing parents for manifestations of characteristics of these disorders – and related illnesses, such as depression and anxiety – may provide a more accurate method of predicting the prevalence and potential severity of the disorders in children. affected children. than just screening for genetic variants. This is likely due, at least in part, to genetic variants that parents pass on to their child that would not be routinely detected in genetic screening and would lead to more serious illnesses, the researchers explained.

An article describing the research appears in American Journal of Human Genetics. According to the researchers, understanding how both parents contribute to their children’s diagnosis could inform genetic counseling and the development of therapeutic intervention plans for children affected by these diseases.

“We observed the presence of neurodevelopmental and psychiatric features in children and parents from a large set of families,” said Santhosh Girirajan, interim department head and T. Ming Chu Professor of Biochemistry and Molecular Biology in the Penn State Eberly College of Science, and author main part of the article. “We observed an increase in the presence of neurodevelopmental disorders in children whose parents reported having the trait, including psychiatric traits such as anxiety or depression.”

The team analyzed 97,000 families, many including children with neurodevelopmental disorders such as autism or intellectual disability, and assessed how risk factors – genetic characteristics and the presence of the characteristics – in both parents impact the trajectory of the disease in children. The datasets included genetic information and questionnaire data from families in a large public biobank, as well as from families from specific studies of neurodevelopmental disorders.

The researchers screened parents and their children for symptoms of several disorders and evaluated known genetic mutations that can give rise to such disorders. Their analysis revealed that parents tend to select partners with the same or related disorders, leading to an increase in the prevalence and potential severity of the disorder in their children.

“Most neurodevelopmental disorders are genetically complex, meaning they are not caused by a single gene,” Girirajan said. “This makes it difficult to trace the exact genetic basis of a disorder in an individual and even more difficult to predict how the disorder will manifest in affected children.”

The researchers explained that complex genetic diseases can be caused by mutations in many genes, each of which can be inherited from one or both parents, or occur spontaneously in the child’s newly formed genome. The prognosis of a child’s disease results from the combination of mutations that the child inherits and how they interact with each other during development. This is called the “multi-hit model” because the disease results from multiple different mutations in many different genes.

“We have been studying one such mutation – a deletion of a small segment of chromosome 16 – that has been implicated as a risk factor for several neurodevelopmental disorders,” Girirajan said. Symptoms of these disorders can manifest as seizures, schizophrenic features, depression, and anxiety, along with features related to addiction.

“This mutation is often passed from parent to child, but the child regularly shows more severe symptoms of the disorder than the parent. We wanted to know whether other ‘hits’ of the disorder could come from the other parent. So we looked at the characteristics of both parents. in a large group of families with children with neurodevelopmental disorders,” Girirajan added.

The research team found that the parent who passed on the deletion had less severe symptoms than their child, or even different but related psychiatric disorders such as depression or anxiety. They also found that the other parent often had similar psychiatric characteristics.

“What we’ve noticed, and it’s been studied for a long time, is that in people there is a phenomenon called ‘assortative mating,'” said Corrine Smolen, a graduate student at Penn State who works with Girirajan and first author on the paper. “Whether consciously or unconsciously, people with similar characteristics preferably find each other as partners. While there may be other explanations, we see this in our data and this is likely what is driving what we are seeing in the families we study. “

The parent who does not have the deletion must have these characteristics due to some other genetic mutations, the researchers explained, and when these mutations are combined with the deletion in the child’s genome, the result is a more serious disease.

By evaluating the characteristics of both parents, researchers were able to more accurately predict the trajectory of the disease in their children than would be possible through genetic screening alone. They could also eventually use this information to try to identify new mutations – those inherited from parents without the deletion – that are involved in causing these characteristics.

“We found that there is a good correlation between parental characteristics,” Girirajan said. “Someone with schizophrenia is more likely to find a partner with schizophrenia, someone with anxiety and depression is more likely to find a partner with anxiety and depression. This is well known for other things, like tall people marrying other tall people. Because All of these traits have at least some genetic component that can be similar between partners, this leads to a situation that is similar to – but less pronounced – consanguineous marriage, when people who are related by ancestry marry.”

In this case, Girirajan explained, selective mating based on traits – rather than kinship – appears to be generating genetic similarity between partners, which could be leading to more cases and potentially more serious traits in their offspring.

For example, researchers observed that when neither partner had anxiety, 12.6% of male children had anxiety. This number jumped to 25.7% when one parent reported having anxiety and to 33.8% when both parents had anxiety. This increase in prevalence is indicative of an increase in severity, because more serious features are more likely to be identified, according to the research team.

More information:
Corrine Smolen et al, Assortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressed variants, The American Journal of Human Genetics (2023). DOI: 10.1016/j.ajhg.2023.10.015

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