Abstract
Disease-associated variants can lead to variable phenotypic outcomes in neurodevelopmental disorders, but the biological mechanisms underlying this variability remain poorly understood. Here, we develop a framework to investigate this phenomenon using the 16p12.1 deletion as a paradigm of variable expressivity. Using induced pluripotent stem cell models from affected families and CRISPR-edited lines with the 16p12.1 deletion, we find that the deletion and rare variants in the genetic background jointly influence chromatin accessibility and expression of neurodevelopmental genes. Cellular analyses identify family-specific phenotypes, including altered inhibitory neuron production and neural progenitor cell proliferation, which correlate with head-size variation. CRISPR activation of individual 16p12.1 genes variably rescue these defects by modulating key developmental signaling pathways. Integrative analyses further identify regulatory hubs, including transcription factors FOXG1 and JUN, as mediators of these effects. Our study provides a functional framework for investigating how individual genetic architectures contribute to phenotypic variability in neurodevelopmental disorders.
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Acknowledgements
The authors thank Dr. Yingwei Mao for valuable advice on iPSC culture and Dr. Melissa Rolls for providing imaging resources. The authors thank Isa Levy for assisting with image quantification. We are grateful to the National Institute of Neurological Disorders and Stroke (NINDS) for supplying iPSC lines derived from healthy donors. The authors thank Dr. Matthew Jensen, Dr. Francisca Canzar, and Johnathan Ray for their assistance and insights in data analysis. S.G. discloses support for the research of this work from NIH R01-GM121907 and NIH R21-NS122398.
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J.S. and S.G. intend to file a provisional patent application related to this work. All other authors declare no competing interests.
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Sun, J., Noss, S., Smolen, C. et al. Functional impact of genetic background on variable expressivity in neurodevelopmental disorders. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72598-z
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DOI: https://doi.org/10.1038/s41467-026-72598-z
