Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome

article Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome published yes Alma Kuechler author Alexander Zink author Thomas Wieland author Hermann Lüdecke author Kirsten Cremer author Leonardo Salviati author Pamela Magini author Kimia Najafi author Christiane Zweier author Johanna Czeschik author Stefan Aretz author Sabine Endele author Federica Tamburrino author Claudia Pinato author Maurizio Clementi author Jasmin Gundlach author Carina Maylahn author Laura Mazzanti author Eva Wohlleber author Thomas Schwarzmayr author Roxana Kariminejad author Avner Schlessinger author Dagmar Wieczorek author Tim Strom author Gaia Novarino author 3E57A680-F248-11E8-B48F-1D18A9856A870000-0002-7673-7178 Hartmut Engels author GaNo department Intellectual disability (ID) has an estimated prevalence of 2-3%. Due to its extreme heterogeneity, the genetic basis of ID remains elusive in many cases. Recently, whole exome sequencing (WES) studies revealed that a large proportion of sporadic cases are caused by de novo gene variants. To identify further genes involved in ID, we performed WES in 250 patients with unexplained ID and their unaffected parents and included exomes of 51 previously sequenced child-parents trios in the analysis. Exome analysis revealed de novo intragenic variants in SET domain-containing 5 (SETD5) in two patients. One patient carried a nonsense variant, and the other an 81 bp deletion located across a splice-donor site. Chromosomal microarray diagnostics further identified four de novo non-recurrent microdeletions encompassing SETD5. CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions. In silico domain prediction of SETD5, a predicted SET domain-containing histone methyltransferase (HMT), substantiated the presence of a SET domain and identified a novel putative PHD domain, strengthening a functional link to well-known histone-modifying ID genes. All six patients presented with ID and certain facial dysmorphisms, suggesting that SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype. The present report of two SETD5 LoF variants in 301 patients demonstrates a prevalence of 0.7% and thus SETD5 variants as a relatively frequent cause of ID. Nature Publishing Group2015 eng European Journal of Human Genetics 25138099 00035447460001310.1038/ejhg.2014.165 236753 - 760 Kuechler, Alma, Alexander Zink, Thomas Wieland, Hermann Lüdecke, Kirsten Cremer, Leonardo Salviati, Pamela Magini, et al. “Loss-of-Function Variants of SETD5 Cause Intellectual Disability and the Core Phenotype of Microdeletion 3p25.3 Syndrome.” European Journal of Human Genetics. Nature Publishing Group, 2015. <a href="https://doi.org/10.1038/ejhg.2014.165">https://doi.org/10.1038/ejhg.2014.165</a>. A. Kuechler, A. Zink, T. Wieland, H. Lüdecke, K. Cremer, L. Salviati, P. Magini, K. Najafi, C. Zweier, J. Czeschik, S. Aretz, S. Endele, F. Tamburrino, C. Pinato, M. Clementi, J. Gundlach, C. Maylahn, L. Mazzanti, E. Wohlleber, T. Schwarzmayr, R. Kariminejad, A. Schlessinger, D. Wieczorek, T. Strom, G. Novarino, H. Engels, European Journal of Human Genetics 23 (2015) 753–760. Kuechler A, Zink A, Wieland T, et al. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. European Journal of Human Genetics. 2015;23(6):753-760. doi:<a href="https://doi.org/10.1038/ejhg.2014.165">10.1038/ejhg.2014.165</a> Kuechler, A., Zink, A., Wieland, T., Lüdecke, H., Cremer, K., Salviati, L., … Engels, H. (2015). Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. European Journal of Human Genetics. Nature Publishing Group. <a href="https://doi.org/10.1038/ejhg.2014.165">https://doi.org/10.1038/ejhg.2014.165</a> Kuechler, Alma, et al. “Loss-of-Function Variants of SETD5 Cause Intellectual Disability and the Core Phenotype of Microdeletion 3p25.3 Syndrome.” European Journal of Human Genetics, vol. 23, no. 6, Nature Publishing Group, 2015, pp. 753–60, doi:<a href="https://doi.org/10.1038/ejhg.2014.165">10.1038/ejhg.2014.165</a>. Kuechler A, Zink A, Wieland T, Lüdecke H, Cremer K, Salviati L, Magini P, Najafi K, Zweier C, Czeschik J, Aretz S, Endele S, Tamburrino F, Pinato C, Clementi M, Gundlach J, Maylahn C, Mazzanti L, Wohlleber E, Schwarzmayr T, Kariminejad R, Schlessinger A, Wieczorek D, Strom T, Novarino G, Engels H. 2015. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. European Journal of Human Genetics. 23(6), 753–760. A. Kuechler et al., “Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome,” European Journal of Human Genetics, vol. 23, no. 6. Nature Publishing Group, pp. 753–760, 2015. 17892018-12-11T11:54:01Z2025-09-23T09:30:27Z