Predicting neurodevelopmental diseases in children from parental characteristics

It is difficult to predict the course of neurodevelopmental and psychiatric disorders like autism or schizophrenia because they can be influenced by many different genetic and environmental factors.

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

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

“We looked at the presence of neurodevelopmental and psychiatric traits in children and parents from a large number of families,” said Santhosh Girirajan, interim department head and T. Ming Chu Professor of Biochemistry and Molecular Biology at Penn. State Eberly College of Science. and lead author of the article. “We saw an increase in the presence of neurodevelopmental disorders in children whose parents both report having this trait, including psychiatric traits like anxiety or depression.”

The team examined 97,000 families, many of which included children with neurodevelopmental disorders such as autism or intellectual disability, and assessed the impact of risk factors (genetic characteristics and the presence of these traits) in both parents on the trajectory of illness in children. The datasets included genetic information and questionnaire data from families in a large public biobank, as well as families from specific studies of neurodevelopmental disorders.

Researchers assessed symptoms of various disorders in parents and their children and assessed known genetic mutations that could give rise to such disorders. Their analysis found that parents tend to select partners with the same or related disorders, leading to increased 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 underpinnings 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 arise spontaneously in the child’s newly formed genome. A child’s disease prognosis results from the combination of mutations he or she inherits and how they interact with each other during development. This is called the “multiple hit model” because the disease results from multiple different mutations in many different genes.

“We studied one of these mutations – 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, and addiction-related features.

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

The research team found that the parent who had 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 exhibited similar psychiatric traits.

“What we realized, and this has been studied for a long time, is that in humans there is a phenomenon called ‘assortative mating,'” said Corrine Smolen, a Penn State graduate student working with Girirajan and first author of the article. “Whether consciously or unconsciously, people with similar characteristics preferentially find each other as partners. While there may be other explanations, we see it in our data and it’s likely what leads to what we let’s observe in the families we studied.”

The parent who does not have a deletion must have these characteristics due to 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 severe disease. .

By assessing 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 testing alone. They could also potentially use this information to try to identify new mutations – those inherited from the parent without deletion – that are involved in the appearance of these traits.

“We found that there is a good correlation between the parents’ traits,” Girirajan said. “A person with schizophrenia is more likely to find a partner with schizophrenia, a person with anxiety and depression is more likely to find a partner with anxiety and depression. This is well known for other things , such as tall people marrying other tall people. Because all If some of these traits have at least one genetic component that might be similar between partners, this leads to a situation that is similar, but less pronounced, in consanguineous marriage, when people linked by ancestry marry.

In this case, Girirajan explained, assortative mating based on traits – rather than relatedness – appears to be causing genetic similarity between partners, which could lead to more cases and traits potentially more serious in their offspring.

For example, researchers found that when neither partner suffered from anxiety, 12.6% of their male children suffered from anxiety. This number rose to 25.7% when one parent reported having anxiety and to 33.8% when both parents had anxiety. This increase in prevalence indicates an increase in severity, as more severe traits are more likely to be identified, according to the research team.