In the table below, we have listed published genes/mutations that were assessed in the PRiSM screen. Note that in cases where we state ‘inconclusive’ there are two possible outcomes: either the variant is not pathogenic, or the PRiSM screen is not able to identify pathogenic variants for that particular gene.
| Gene | Published | Prism Results Published | Pathogenic | Knockdown |
| CACNG2 (V134L) | Hamdan et al., 2011 | No | Yes (LoF) | N.A. |
| CAMK2A (E109D) | Kury et al., 2017 | Yes | Yes (GoF) | no effect |
| CAMK2A (E183V) | lossifov et al., 2014; Stephenson et al., 2017; Kury et al., 2017 | Yes | Yes (LoF) | no effect |
| CAMK2A (F98S) | Kury et al., 2017 | Yes | Yes (LoF) | no effect |
| CAMK2A (H282R) | Kury et al., 2017 | Yes | Yes (GoF) | no effect |
| CAMK2A (P138A) | Kury et al., 2017 | Yes | Yes (LoF) | no effect |
| CAMK2A (P212L) | Kury et al., 2017 | Yes | Yes (LoF) | no effect |
| CAMK2A (P235L) | Kury et al., 2017 | Yes | incoclusive | no effect |
| CAMK2A (T286P) | Kury et al., 2017 | Yes | Yes (GoF) | no effect |
| CAMK2B (E110K) | Kury et al., 2017 | Yes | Yes (GoF) | Damaging |
| CAMK2B (E237K) | Kury et al., 2017 | Yes | Yes (GoF) | Damaging |
| CAMK2B (K301E) | Kury et al., 2017 | Yes | Yes (LoF) | Damaging |
| CAMK2B (P139L) | Kury et al., 2017 | Yes | Yes (GoF) | Damaging |
| CAMK2G (K292P) | De ligt et al., 2012; Proietti Onori et al., 2018 | Yes | Yes (GoF) | Damaging |
| COL4A3BP (S266C) | De ligt et al., 2012 | No | incoclusive | N.A. |
| GRIA1 (A636T) | De ligt et al., 2012 | No | yes | N.A. |
| GRIN2A (L649V) | De ligt et al., 2012 | No | yes | no effect |
| GRIN2B (P553L) | De ligt et al., 2012 | No | Yes (LoF) | Damaging |
| KIF5C (E237K) | De ligt et al., 2012 | No | yes | N.A. |
| KIF5C (E237V) | Poirier et al., 2013 | No | yes | N.A. |
| MIB (R174H) | De ligt et al., 2012 | No | incoclusive | N.A. |
| PHACTR1 (R521C) | De ligt et al., 2012 | No | incoclusive | N.A. |
| PPP2R5D (P53S) | De ligt et al., 2012 | No | incoclusive | N.A. |
| PPP2R5D (W207R) | Houge et al., 2015 | No | yes | N.A. |
| PROX2 (R474H) | De ligt et al., 2012 | No | incoclusive | N.A. |
| PSMA7 (A112D) | De ligt et al., 2012 | No | Yes (LoF) | N.A. |
| RAC1 (C18Y) | Reijnders et al., 2017a | No | incoclusive | Damaging |
| RAC1 (N39S) | Reijnders et al., 2017a | No | incoclusive | Damaging |
| RHEB (P37L) | Reijnders et al., 2017b | Yes | Yes (GoF) | Damaging |
| RHEB (S68P) | Reijnders et al., 2017b | Yes | Yes (GoF) | Damaging |
| TUSC3 (M247V) | De ligt et al., 2012 | No | incoclusive | N.A. |
Table 1: List of mutations tested using the PRiSM screen. The initial mutations tested came from a list of candidate mutations for intellectual disability from several published whole exome sequencing studies. The results of these will be published in the near future. For some of the genes tested we have also assessed the effect of knockdown. Damaging means that in at least one of our assays we saw an effect of the knockdown. N.A. = not assessed
Cited references:
Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., et al. (2011). Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability. The American Journal of Human Genetics, 88(3), 306–316. http://doi.org/10.1016/j.ajhg.2011.02.001
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., et al. (2012). Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability. The New England Journal of Medicine, 367(20), 1921–1929. http://doi.org/10.1056/NEJMoa1206524
Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., et al. (2013). Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nature Genetics, 45(6), 639–647. http://doi.org/10.1038/ng.2613
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., et al. (2014). The contribution of de novo coding mutations to autism spectrum disorder. Nature, 515(7526), 216–221. http://doi.org/10.1038/nature13908
Houge, G., Haesen, D., Vissers, L. E. L. M., Mehta, S., Parker, M. J., Wright, M., et al. (2015). B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. Journal of Clinical Investigation, 125(8), 3051–3062. http://doi.org/10.1172/JCI79860
Küry, S., van Woerden, G. M., Besnard, T., Proietti Onori, M., Latypova, X., Towne, M. C., et al. (2017). De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. American Journal of Human Genetics, 101(5), 768–788. http://doi.org/10.1016/j.ajhg.2017.10.003
Reijnders, M. R. F., Ansor, N. M., Kousi, M., Yue, W. W., Tan, P. L., Clarkson, K., et al. (2017a). RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes. American Journal of Human Genetics, 101(3), 466–477. http://doi.org/10.1016/j.ajhg.2017.08.007
Reijnders, M. R. F., Kousi, M., van Woerden, G. M., Klein, M., Bralten, J., Mancini, G. M. S., et al. (2017b). Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability. Nature Communications, 8(1), 1052. http://doi.org/10.1038/s41467-017-00933-6
Stephenson, J. R., Wang, X., Perfitt, T. L., Parrish, W. P., Shonesy, B. C., Marks, C. R., et al. (2017). A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors. Journal of Neuroscience, 37(8), 2216–2233. http://doi.org/10.1523/JNEUROSCI.2068-16.2017
Proietti Onori, M., Koopal, B., Everman, D. B., Worthington, J. D., Jones, J. R., Ploeg, M. A., et al. (2018). The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function. Human Mutation. http://doi.org/10.1002/humu.23647