Parental traits offer new clues to predicting neurodevelopmental disorders in children

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The course of neurodevelopmental and psychiatric disorders such as autism or schizophrenia is difficult to predict because they can be influenced by various genetic and environmental factors. A new study, led by Penn State researchers, shows that assessing parents for manifestations of these disorder characteristics -; and related diseases such as depression and anxiety -; May provide a more accurate method of predicting the prevalence and potential severity of disorders in affected children than screening for genetic variants alone. This is likely, at least in part, due to genetic variants that parents pass on to children that would not be routinely picked up in genetic screens and lead to more severe disease, the researchers explained.

A paper describing the research has been published American Journal of Human Genetics. According to the researchers, understanding how both parents contribute to their child’s diagnosis can inform genetic counseling and the development of therapeutic intervention plans for children affected by these disorders.

We looked at the presence of neurodevelopmental and emotional characteristics in children and parents in a large group of families. “We have seen an increased incidence of neurodevelopmental disorders in children whose parents both report these traits, including psychotic features such as anxiety or depression.”


Santosh Girirajan, interim department head and professor of biochemistry and molecular biology at Penn State Eberly College of Science, T. Ming Chu and lead author of the paper

The team looked at 97,000 families, many of whom had children with neurodevelopmental disorders such as autism or intellectual disabilities, and assessed risk factors -; Presence of genetic traits and characteristics -; Both parents influence the course of the disease 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 evaluated parents and their children for symptoms of various diseases and identified known genetic mutations that could lead to such disorders. Their analysis found that parents tend to select partners with the same or related disorders, thereby increasing the prevalence and potentially severity of the disorder in their children.

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

Researchers explain 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 a child’s newly formed genome. Disease prognosis in children depends on the combination of mutations they inherit and how they interact with each other during development. This is called the “multi-hit model” because the disease is caused by multiple different mutations in different genes.

“We are studying one such mutation—a deletion of a small portion of chromosome 16—that has been implicated as a risk factor for various neurodevelopmental disorders,” Girirajan said. Symptoms of these disorders can manifest as seizures, schizophrenic features, depression, and anxiety, along with features associated with addiction. “This mutation is often passed from one parent to a child, but the child regularly has more severe symptoms of the disorder than the parent. We wanted to know if another ‘hit’ for the disorder could come from the other parent. So, “we neurodevelopmental observed characteristics of both parents in a large cohort of families with children with the disorder.”

The research team found that parents who had deletions had less severe symptoms than their children or even different but related mental disorders such as depression or anxiety. They also found that other parents often had similar emotional characteristics.

“What we’ve come to understand, and it’s been studied for a long time, is that there’s a phenomenon in humans called ‘assortative mating,'” said Penn State graduate student Corinne Smolen, who worked with Girirajan and is the paper’s first author. “Whether consciously or unconsciously, people with similar characteristics tend to find each other as partners by choice. While there may be other explanations, this is what we see in our data, and it’s likely what we’re seeing in the families we’ve studied.”

The parent who doesn’t carry the deletion must have these traits because there are other genetic mutations, the researchers explained, and when these mutations are combined with deletions in the child’s genome, the result is more severe disease. By assessing the characteristics of both parents, researchers can more accurately predict the course of the disease in their children than would be possible only through genetic screening. They may eventually use this information to try to identify new mutations -; Those inherited from parents without deletion -; That is involved in causing this feature.

“We found that there was 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, such as tall people marrying other tall people. Because everyone has at least some genetic component to these traits. have which may be similar between the partners, leading to a situation similar, but less pronounced, to consanguineous marriage, when people related by ancestry marry.”

In this case, Girirajan explained, based on the Sanghabanda Sangam feature -; rather relation -; Partners appear to have genetic similarities that may lead to more cases and potentially more severe traits in their children. For example, researchers found that when neither partner had anxiety, 12.6% of their male children had anxiety. This number jumped to 25.7% when one parent reported having anxiety and 33.8% when both parents had anxiety. This increase in prevalence indicates an increase in severity because more severe features are more likely to be identified, according to the research team.

In addition to Girirajan and Smolen, the research team includes Matthew Jensen, Lucilla Pizzo, Anastasia Tyrishkina, Depro Banerjee, Laura Rohan and Emily Huber of Penn State; Lisa Dyer and Jane Jussola at ZNDX in Maryland; Laila El Khattaby at Assistance Public–Hopitaux de Paris in France; Paolo Prontera at Santa Maria della Misericordia Hospital, Italy; Jean-Hubert Caberg at the Universitaire de Liege, Center Hospitalier, Belgium; Anke van Dijk at the University and University Hospital Antwerp in Belgium and R. Frank Coy; Charles Schwartz at the Greenwood Genetic Center in South Carolina; Laurence Favre, Patrick Callier, and Mathilde Lefebvre at the Université de Bourgogne in France; Anne-Laure Mosca-Boydron at the Laboratory de Genetic Chromosomal et Molecular in France; Kate Pope, Penny Snell and Paul J. of the University of Melbourne, Australia. Lockhart; David J Amore at the Murdoch Children’s Research Institute in Australia; Lucia Castiglia, Ornella Galesi, Emanuela Avola and Maria Grazia Brucheri at the OC Research Institute in Italy; Teresa Mattina, Marco Fichera and Corrado Romano of the University of Catania, Italy; Giuseppe Maria Luana Mandara in ASP Ragusa, Italy; Olivier Pichon, Silvestre Cuinat, Sandra Mercier, Claire Bénéteau and Bertrand Isidor at CHU Nantes, France; Cédric Le Cagnac of the University of Toulouse, France; Radka Stoeva at CHU de Le Mans, France; Sophie Blason and Dominique Martin-Coinard at Bretonau University Hospital, France; Ashley Nordsletten of the University of Michigan; and Eric Sistermans at Amsterdam UMC in the Netherlands.

Grants from the US National Institutes of Health, the South Carolina Department of Disabilities and Special Needs, and the Italian Ministry of Health-Riserca Corrente supported the research.

Source:

Journal Reference:

Smolen, C., etc. (2023). Assortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressed variants. American Journal of Human Genetics. doi.org/10.1016/j.ajhg.2023.10.015.



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