title: Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.
abstract: 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.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zink
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Lüdecke
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.affiliation: Department Salute Donna e Bambino, Clinical Genetics Unit, University of Padova, Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: U.O. Genetica Medica, Dipartimento d Scienze Mediche e Chirugiche (D.I.M.E.C.), Università di Bologna, Bologna, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Magini
authors.affiliation: Kariminejad Najmabadi Pathology and Genetics Center, Shahrak Gharb, Tehran, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Najafi
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Johanna Christina
authors.initials: JC
authors.lastname: Czeschik
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Endele
authors.affiliation: Ambulatorio di Auxologia, Sindromologia e Malattie Rare, Dipartimento di Scienze Mediche e Chirurgiche (D.I.M.E.C.), Università di Bologna, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Tamburrino
authors.affiliation: Department Salute Donna e Bambino, Clinical Genetics Unit, University of Padova, Padova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pinato
authors.affiliation: Department Salute Donna e Bambino, Clinical Genetics Unit, University of Padova, Padova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Clementi
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Gundlach
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Maylahn
authors.affiliation: Ambulatorio di Auxologia, Sindromologia e Malattie Rare, Dipartimento di Scienze Mediche e Chirurgiche (D.I.M.E.C.), Università di Bologna, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wohlleber
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzmayr
authors.affiliation: Kariminejad Najmabadi Pathology and Genetics Center, Shahrak Gharb, Tehran, Iran.
authors.forename: Roxana
authors.initials: R
authors.lastname: Kariminejad
authors.affiliation: Department of Pharmacology and Systems Therapeutics, and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Avner
authors.initials: A
authors.lastname: Schlessinger
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Science and Technology Austria, Klosterneuburg, Austria.
authors.forename: Gaia
authors.initials: G
authors.lastname: Novarino
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D018389:Codon, Nonsense; D059472:Exome; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D013577:Syndrome; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D008780:Methyltransferases; C000588437:SETD5 protein, human