Tested Genes

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. 

GenePublishedPrism Results PublishedPathogenicKnockdown
CACNG2 (V134L)Hamdan et al., 2011NoYes (LoF)N.A.
CAMK2A (E109D)Kury et al., 2017YesYes (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 incoclusiveno 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
YesYes (GoF)Damaging
COL4A3BP (S266C)De ligt et al., 2012 NoincoclusiveN.A.
GRIA1 (A636T)De ligt et al., 2012 No yesN.A.
GRIN2A (L649V)De ligt et al., 2012 No yesno effect
GRIN2B (P553L)De ligt et al., 2012 No Yes (LoF)Damaging
KIF5C (E237K)De ligt et al., 2012 No yesN.A.
KIF5C (E237V)Poirier et al., 2013 No yesN.A.
MIB (R174H) De ligt et al., 2012 No incoclusiveN.A.
PHACTR1 (R521C) De ligt et al., 2012 No incoclusiveN.A.
PPP2R5D (P53S) De ligt et al., 2012
No incoclusiveN.A.
PPP2R5D (W207R)Houge et al., 2015
No yesN.A.
PROX2 (R474H) De ligt et al., 2012 No incoclusiveN.A.
PSMA7 (A112D) De ligt et al., 2012 No Yes (LoF)N.A.
RAC1 (C18Y)Reijnders et al., 2017a No incoclusiveDamaging
RAC1 (N39S)Reijnders et al., 2017a No incoclusiveDamaging
RHEB (P37L)Reijnders et al., 2017bYesYes (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