People with the same deletion on part of chromosome 16 are at risk of developing neurodevelopmental disorders, although some experience severe intellectual disability and developmental delays, while others only exhibit milder psychiatric symptoms such as depression and anxiety. How can this happen?
To answer this, a team led by scientists at Penn State University has developed a method that assesses how genetic variations elsewhere in an individual’s genome interact with deletions to help determine the traits that individual expresses. The researchers said that instead of the traditional focus on single causative mutations in neurodevelopmental disorders, this study shifts emphasis to the role of interactions between a patient’s entire genetic makeup, which could inform personalized and precision medical interventions for complex disorders.
A paper describing the research is available online in the journal Nature Communications.
Many traits are known to have a complex genetic basis. In other words, the way a trait appears is influenced by interactions between many genes. For more than 10 years, we have been studying a deletion on chromosome 16 called 16p12.1. This deletion deletes eight genes and is associated with a variety of neurodevelopmental outcomes, including autism, developmental delay, and birth defects. Although we have been studying deletions in the Drosophila model and at the human population level, we wanted to see if we could dig deeper to understand how the clinical features of deletions vary from family to family. ”
Santhosh Girirajan, T. Ming Chu Professor of Genomics, Chair of the Department of Chemistry and Molecular Biology, Penn State Eberly College of Science, and research team leader
The researchers explained that unlike many other genetic diseases, which are often caused by a new mutation in an individual, in most cases, patients with the 16p12.1 deletion inherited the gene from a parent with the mutation but may not have any clinical features to diagnose it.
“Children who inherit a deletion from one parent receive half their genome from the other parent,” Girirajan said. “This new combination of genetic information in children can expose the deletion to a different set of genetic variations than the parent without the deletion, which can interact to cause different traits. It can also help us compare family members to identify secondary genetic variations that may influence the traits that emerge and their severity.”
To find out why individuals from different families differ, the researchers used two strategies. The first strategy used induced pluripotent stem cells (iPSCs) derived from 16p12.1 deletion patients, their families, and healthy donors. iPSCs were derived from blood samples donated by patients and their families, and controls from healthy donors were provided by the National Institute of Neurological Disorders and Stroke.
“Induced pluripotent stem cells (iPSCs), generated by reprogramming blood or skin cells, can differentiate into many cell types,” said Jiawan Sun, a graduate student in Molecular, Cellular, and Integrative Biosciences at Penn State and co-first author of the paper. “By adding specific small molecules, we can differentiate them into different cell types within the neuronal lineage and compare gene expression in cells from different families and in cells with and without the deletion.”
The research team converted iPSCs into neuron precursors called neural progenitor cells, as well as immature and mature neurons. They also used CRISPR gene editing technology to induce deletions in iPSCs from healthy donors. Some of these cell lines with deletions developed abnormal cell proliferation, cell death, and premature differentiation that varied between individuals. These abnormalities are consistent with some clinical features of individuals with the 16p12.1 deletion, such as changes in head size, which have also been reported in studies of autism and schizophrenia, the researchers said.
The researchers identified rare variations in each individual’s genetic background by completely sequencing the genome of each cell line used in the study. They also quantified the expression levels of all genes in each cell type. From this data, the research team found that the genetic background of the iPSC lines contributed to specific changes in gene expression between individual cell lines. They also found differences between cell lines in the accessibility of genomic regions that do not code for genes but may help control the expression of other genes.
“Studies are being done that compare cell lines with a particular mutation to identical cells without the mutation, or look at entire groups of individuals to find common genetic traits shared by the group,” Girirajan said. “What makes our study unique is our ability to identify variation in family-specific genetic backgrounds.”
The research team also observed interactions with the genetic background of healthy donor cells carrying the CRISPR-induced 16p12.1 deletion. The researchers explained that this shows that even healthy people can carry genetic variations that can contribute to neurodevelopmental disorders in situations involving deletions, which can influence the risk to children.
The second strategy the team used to uncover differences in clinical features associated with the 16p12.1 deletion was to use CRISPR gene editing to restore function of the genes within the deletion one by one. They found that each restored gene affected the expression of an independent set of genes that varied between families and cell types in their study.
“We thought that the variation we see between individuals was driven by what we call the ‘two-hit’ model,” said Selina Noss, a graduate student in Molecular, Cellular, and Integrative Life Sciences at Penn State University and co-first author of the paper. “While this deletion is the first hit and may interact with mutations in the second hit elsewhere in the genome, we moved away from that language because we found that the deletion interacted with multiple mutations throughout the individual’s genome. This is actually more of a multi-hit model.”
The researchers said this multi-hit model and understanding how an individual’s genetic makeup contributes to complex neurodevelopmental disorders could help develop personalized treatments for these disorders.
In addition to Girirajan, Sun, and Noss, the Penn State research team included bioinformatics and genomics graduate students Corinne Smolen and Deepro Banerjee. Venkata Hemanjani Bhavana, graduate student in biochemistry and molecular biology. Maitreya Das, graduate student in molecular, cellular, and integrative life sciences; Belinda Jardin, computer programmer. and Anisha Prabhu, an undergraduate student in biochemistry and molecular biology. The team also included David J. Amor, Kate Pope, and Paul J. Lockhart of the University of Melbourne, Australia.
The National Institutes of Health funded the study.
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Reference magazines:
Sun, J. others. (2026). Functional influence of genetic background on diverse expressive abilities in neurodevelopmental disorders. nature communications. DOI: 10.1038/s41467-026-72598-z. https://www.nature.com/articles/s41467-026-72598-z
