Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

Marcogliese, P. C.; Deal, S. L.; Andrews, J.; Harnish, J. M.; Bhavana, V. H.; Graves, H. K.; Jangam, S.; Luo, X.; Liu, N.; Bei, D.; Chao, Y.-H.; Hull, B.; Lee, P.-T.; Pan, H.; Longley, C. M.; Chao, H.-T.; Chung, H.; Haelterman, N. A.; Kanca, O.; Manivannan, S. N.; Rossetti, L. Z.; Gerard, A.; Schwaibold, E. M. C.; Guerrini, R.; Vetro, A.; England, E.; Murali, C. N.; Barakat, T. S.; van Dooren, M. F.; Wilke, M.; van Slegtenhorst, M.; Lesca, G.; Sabatier, I.; Chatron, N.; Brownstein, C. A.; Madden, J. A.; Agrawal, P. B.; Keller, R.; Pavinato, L.; Brusco, A.; Rosenfeld, J. A.; Marom, R.; Wangler,

doi:10.1101/2020.12.30.424813

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bioRxiv · 10.1101/2020.12.30.424813

Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

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Abstract

Individuals with autism spectrum disorders (ASD) exhibit an increased burden of de novo variants in a broadening range of genes. We functionally tested the effects of ASD missense variants using Drosophila through humanization rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identified GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

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Marcogliese, P. C., Deal, S. L., Andrews, J., Harnish, J. M., Bhavana, V. H., Graves, H. K., Jangam, S., Luo, X., Liu, N., Bei, D., Chao, Y.-H., Hull, B., Lee, P.-T., Pan, H., Longley, C. M., Chao, H.-T., Chung, H., Haelterman, N. A., Kanca, O., Manivannan, S. N., Rossetti, L. Z., Gerard, A., Schwaibold, E. M. C., Guerrini, R., Vetro, A., England, E., Murali, C. N., Barakat, T. S., van Dooren, M. F., Wilke, M., van Slegtenhorst, M., Lesca, G., Sabatier, I., Chatron, N., Brownstein, C. A., Madden, J. A., Agrawal, P. B., Keller, R., Pavinato, L., Brusco, A., Rosenfeld, J. A., Marom, R., Wangler,. 2021-01-01. Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases. https://doi.org/10.1101/2020.12.30.424813

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