---
_id: '1789'
abstract:
- lang: eng
text: 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.
article_processing_charge: No
author:
- first_name: Alma
full_name: Kuechler, Alma
last_name: Kuechler
- first_name: Alexander
full_name: Zink, Alexander
last_name: Zink
- first_name: Thomas
full_name: Wieland, Thomas
last_name: Wieland
- first_name: Hermann
full_name: Lüdecke, Hermann
last_name: Lüdecke
- first_name: Kirsten
full_name: Cremer, Kirsten
last_name: Cremer
- first_name: Leonardo
full_name: Salviati, Leonardo
last_name: Salviati
- first_name: Pamela
full_name: Magini, Pamela
last_name: Magini
- first_name: Kimia
full_name: Najafi, Kimia
last_name: Najafi
- first_name: Christiane
full_name: Zweier, Christiane
last_name: Zweier
- first_name: Johanna
full_name: Czeschik, Johanna
last_name: Czeschik
- first_name: Stefan
full_name: Aretz, Stefan
last_name: Aretz
- first_name: Sabine
full_name: Endele, Sabine
last_name: Endele
- first_name: Federica
full_name: Tamburrino, Federica
last_name: Tamburrino
- first_name: Claudia
full_name: Pinato, Claudia
last_name: Pinato
- first_name: Maurizio
full_name: Clementi, Maurizio
last_name: Clementi
- first_name: Jasmin
full_name: Gundlach, Jasmin
last_name: Gundlach
- first_name: Carina
full_name: Maylahn, Carina
last_name: Maylahn
- first_name: Laura
full_name: Mazzanti, Laura
last_name: Mazzanti
- first_name: Eva
full_name: Wohlleber, Eva
last_name: Wohlleber
- first_name: Thomas
full_name: Schwarzmayr, Thomas
last_name: Schwarzmayr
- first_name: Roxana
full_name: Kariminejad, Roxana
last_name: Kariminejad
- first_name: Avner
full_name: Schlessinger, Avner
last_name: Schlessinger
- first_name: Dagmar
full_name: Wieczorek, Dagmar
last_name: Wieczorek
- first_name: Tim
full_name: Strom, Tim
last_name: Strom
- first_name: Gaia
full_name: Novarino, Gaia
id: 3E57A680-F248-11E8-B48F-1D18A9856A87
last_name: Novarino
orcid: 0000-0002-7673-7178
- first_name: Hartmut
full_name: Engels, Hartmut
last_name: Engels
citation:
ama: 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:10.1038/ejhg.2014.165
apa: 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. https://doi.org/10.1038/ejhg.2014.165
chicago: 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. https://doi.org/10.1038/ejhg.2014.165.
ieee: 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.
ista: 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.
mla: 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:10.1038/ejhg.2014.165.
short: 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.
date_created: 2018-12-11T11:54:01Z
date_published: 2015-06-15T00:00:00Z
date_updated: 2025-09-23T09:30:27Z
day: '15'
department:
- _id: GaNo
doi: 10.1038/ejhg.2014.165
external_id:
isi:
- '000354474600013'
pmid:
- '25138099'
fulldoi: https://doi.org/10.1038/ejhg.2014.165
intvolume: ' 23'
isi: 1
issue: '6'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795044/
month: '06'
oa: 1
oa_version: Submitted Version
page: 753 - 760
pmid: 1
publication: European Journal of Human Genetics
publication_status: published
publisher: Nature Publishing Group
publist_id: '5324'
quality_controlled: '1'
status: public
title: Loss-of-function variants of SETD5 cause intellectual disability and the core
phenotype of microdeletion 3p25.3 syndrome
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 23
year: '2015'
...