Predicting the development of neurodevelopmental and psychiatric illnesses such as autism or schizophrenia is challenging since they are influenced by a wide range of hereditary and environmental factors. A new study, led by Penn State researchers, shows that evaluating parents for their manifestation of these disorders and related diseases like depression and anxiety may be a more accurate method of predicting the prevalence, and potential severity, of the disorders in affected children than screening for genetic variants alone.
This is most likely attributable, at least in part, to genetic variations passed down from parents to children that would not be detected by a genetic screen and would result in more severe disease, according to the researchers.
The American Journal of Human Genetics published a paper that described the research. According to the researchers, understanding how both parents contribute to their child’s diagnosis can help with genetic counselling and the formulation of therapeutic intervention strategies for children affected by these conditions.
“We looked at the presence of neurodevelopmental and psychiatric traits 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 lead author of the paper. “We saw an increase in the presence of neurodevelopmental disorders in children whose parents both report having the trait, including psychiatric traits like anxiety or depression.”
The team looked at 97,000 families, many including children with neurodevelopmental disorders such as autism or intellectual disability and evaluated how risk factors — genetic features and the presence of the traits — in both parents impact the trajectory of the disease in the 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 evaluated parents and their children for symptoms of the various disorders and assessed 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 increased prevalence and, potentially, severity of the disorder in their children.
“Most neurodevelopmental disorders are genetically complex, meaning that they aren’t caused by a single gene,” Girirajan said. “This makes it hard to trace the exact genetic underpinnings of a disorder in an individual and even harder to predict how the disorder will play out in affected children.”
The researchers explained that complex genetic diseases can be caused by mutations in many genes, each of which could be inherited from one or both parents, or occur spontaneously in the newly formed genome of the child. The child’s disease prognosis results from the combination of mutations that they inherit and how they interact with one another 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 characteristics related to addiction.
“This mutation is often passed from a parent to a child, but the child regularly has more severe symptoms of the disorder than the parent. We wanted to know if other ‘hits’ for the disorder could be coming from the other parent. So, we looked at the traits of both parents in a large cohort of families with children with neurodevelopmental disorders.”
The research team found that the parent that had passed on the deletion had less severe symptoms than their child or even different but related psychiatric disorders like depression or anxiety. They also found that the other parent often had similar psychiatric traits.
“What we realized, 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 working with Girirajan and the first author of the paper. “Whether it’s consciously or unconsciously, people with similar features preferentially find each other as partners. Although there could be other explanations, we see this in our data and that is probably what is leading to what we are seeing in the families that we studied.”
The parent that doesn’t have the deletion must have these traits because of some other genetic mutations, the researchers explained, and when these mutations are combined with the deletion in the genome of the child, the result is more severe disease. By assessing the traits in both parents, the researchers could more accurately predict the trajectory of the disease in their children than would be possible via genetic screening alone. They also could eventually use this information to try to identify new mutations — those inherited from the parent without the deletion — that are involved in causing these traits.
“We found that there is a good correlation between the traits in the parents,” 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 components that could be similar between the partners, this leads to a situation that is akin, but less pronounced, to consanguineous marriage, when people who are related through ancestry marry.”
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