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.

Bainbridge–Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition

“…For patients 3, 4 and 6, exome sequencing was performed as described in Kuechler et al 14 In brief, exomes were enriched using the SureSelect XT Human All Exon 50 Mb kit, versions 3 or 5 (Agilent Technologies), sequencing was performed on HiSeq2000/2500 systems (Illumina). Image analysis and base calling was performed using Illumina Real-Time Analysis.…”

SETD5 gene variant associated with mild intellectual disability - a case report

“…When compared to other studies, our patient shows a milder phenotype, probably due to large deletions encompassing several genes in more severely affected patients (Gunnarsson and Foyn Bruun, 2010;Peltekova et al, 2012;Kuechler et al, 2015;Kellogg et al, 2013).…”

“…Rauch et al (2012) described a new one, Kuechler et al (2015) and Szczałuba et al (2016) described 2 variants each one, and Kobayashi et al (2016) described 1 de novo mutation. These data show that mutations are commonly found in ID.…”

“…De novo CNVs are the most common ID etiology, indicating that monoallelic alterations are sufficient to cause disease by LoF resulting in haploinsufficiency (Hamdan et al, 2009a;Kuechler et al, 2015).…”

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

“…[88][89][90][91] In other microdeletion syndromes, the critical gene is identified when pathogenic point mutations are found in the gene, for example, KANSL1 in 17q21.31 microdeletions 92,93 and SETD5 in 3p25.3 microdeletions. 94 As newer genome-wide technologies such as exome and genome sequencing begin to gain broader clinical use, integration of data from CNV and sequencing studies are becoming another powerful tool to find novel human disease genes. 7 As the density of array coverage over human disease genes increases with improving technologies, smaller CNVs in these genes are being discovered, and genotype-phenotype correlations are being further refined.…”