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Research Article

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

Published: May 25, 2017
Genet.Mol.Res. 16(2): gmr16029615
DOI: 10.4238/gmr16029615


The recent advent of exome sequencing has allowed for the identification of pathogenic gene variants responsible for a variety of diseases that were previously clinically diagnosed, with no underlying molecular etiology. Among these conditions, intellectual disability is a prevalent heterogeneous condition, presenting itself in a large spectrum of intensity, in some cases associated with congenital malformations, behavioral and various other intellectual development alterations. Here we report on a 36-year-old male patient, with a mild intellectual disability that remained undiagnosed at the molecular level for all his life. Using Nextera Exome Sequencing, a Chr3:9.517.294 A>AC (c.3848_3849insC) SETD5 gene insertion was found. This rare variant was classified as likely pathogenic due to its frameshift nature in the gene, in which loss-of-function mutations have been previously reported to cause intellectual disability, as well as a 3p25.3 microdeletion phenotype. It is possible that this variant shows partial activity, due to its gene localization, which would explain the patient’s mild phenotype when compared with other reports.


Intellectual disability (ID) is a group of diseases with cognitive developmental delay. ID is most commonly found during childhood, with prevalence ranging from 1-3% (Hamdan et al., 2009a,b; Rauch et al., 2012).

ID includes phenotypes such as congenital malformation, hypotonia, feeding difficulties, speech and motor deficits, growth retardation, cardiovascular and renal defects, epilepsy, hearing impairment, craniofacial features with brachycephaly and prominent high forehead, and long, thin and tubular nose. Skeletal features include thoracic scoliosis, kyphosis, and lordosis. Furthermore, behavioral issues as obsessive-compulsive disorder and autism are commonly found (Gunnarsson and Foyn Bruun, 2010; Cooper et al., 2011; Grozeva et al., 2014).

Recent studies have identified several mutations in autosomal and X-chromosomes supporting the idea that more than 2000 genes participate in the intellectual development, but the complete genetic basis for ID is still unclear, due in large part to its high heterogeneity (Hamdan et al., 2009a; Rauch et al., 2012; Grozeva et al., 2014).

Currently, next-generation sequencing and microarray studies have identified indels that cause loss of function alterations (LoF) and copy number variation (CNV) in individuals with ID, since all cases have some CNVs, most of which are rated as benign (Hamdan et al., 2009b; Gunnarsson and Foyn Bruun, 2010; Cooper et al., 2011; Rauch et al., 2012; Grozeva et al., 2015). 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).

Recently, SETD5 gene mutations were associated with ID. The SETD5 gene encodes a protein that regulates transcription. Large and small deletions as well nonsense, stop mutations, and frameshift mutations in this gene may result in premature stop codons leading to developmental diseases, as the 3p syndrome and other IDs (Grozeva et al., 2014; Sowalsky et al., 2015).

Here, we report a patient with non-syndromic intellectual disability and a SETD5 C insertion (Chr3p25: 9.517.294).

Materials and Methods

Clinical report

A 36-year-old male patient, with two healthy brothers from nonconsanguineous parents, was clinically diagnosed with mild motor and intellectual disability, myopia, and astigmatism. His physical parameters were normal, weighing 65 kg, 178 cm of height, and a head circumference of 57.5 cm. Brain magnetic resonance and chest echo Doppler showed no morphological alterations. Metabolic tests were all normal. The parents provided a written informed consent for this study.


Patient’s blood was collected and sent to Mendelics Laboratory (São Paulo, Brazil). Sequencing was performed as Nextera Exome Rapid Capture (77-bp paired-end reads; coverage: 97.47% at a minimum of 20 reads) on Illumina HiSeq (Illumina, San Diego, CA, USA). The alignment was based on the GRCh37 human genome assembly. The mutation found was confirmed and parents were also analyzed by Sanger’s sequencing.


Sequencing revealed the Chr3:9.517.294 A>AC variant (or alternatively, c.3848_3849insC - CCDS46741.1) affecting one copy of the SETD5 gene (set domain-containing protein 5, OMIM #615743), and causing the substitution of a serine at position 1286 for leucine; This is a frameshift mutation that creates a premature stop codon (p.Ser1286Leu), at position 1322 (Figure 1). This variant was described as probably pathogenic, with a possible loss of function for the SETD5 gene product. No other variants were reported. Parents tested negative for this particular variant by Sanger’s sequencing, suggesting that this was a de novo mutation (Figure 2).


Figure 1: A. Simplified heredogram. Arrow points to the proband. ID is hash-colored. B. SETD5 gene structure (RefSeq transcript NG_034132.1). C. Wild-type protein sequence (amino acids 1282 to 1325). D. Altered protein sequence: *First altered amino acid; **Stop codon position. Modified from Kuechler et al. (2015).


Figure 2: Sanger’s sequencing electropherogram of the region verified by Sanger sequencing. A. Patient with the variant. B. Father without the variant. C. Mother without the variant.


Although there are several types of intellectual disabilities, they can generally be characterized by specific features such as speech and motor deficits, growth retardation, cardiovascular and renal defects, and behavioral issues such as autism spectrum disorders, obsessive compulsive disorders, and hand flapping behavior (Grozeva et al., 2014; Pinto et al., 2014). These features can vary according to the main underlying genetic cause and genotype-phenotype specific correlations (Riess et al., 2012).

Although rare, patients with IDs may present large deletions (up to 12 Mb), small deletions, substitutions, and insertions (Riess et al., 2012).Our results suggest a new de novo SETD5 gene variant (Chr3:9.517.294/ c.3848_3849insC) as the genetic cause of ID in this patient.

In 2014, Grozeva et al. identified 7 new mutations in the SETD5 gene in patients with ID, including 4 substitutions, 2 deletions, and 1 duplication. Rauch et al. (2012) described a new one, Kuechler et al. (2015) and Szczaluba 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. The 3p syndrome is rare, but well described and commonly caused by de novo mutations (Grozeva et al., 2015).

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).

The 4329-bp SETD5 gene encodes a 1442-amino acid protein, which is highly conserved in mammalian species. SETD5 mRNA is highly expressed in the cerebral cortex, intestine, and the eye, but its exact role is still unclear. Recent studies showed that SETD5 might function as a transcription regulator because similar domains are frequently found in nuclear proteins that interact with chromatin (Grozeva et al., 2015; Kuechler et al., 2015; Sowalsky et al., 2015).

The fact that the SETD5 protein is expressed in the eye may explain vision problems reported in this patient. Our patient shows a small insertion, while most patients have large deletions in genes that participate in the mental and physical development (Kuechler et al., 2015).

Moreover, the reported insertion (c.3848_3849insC) happened at the end of the gene in a disordered region and not in known domains (in silico prediction) (Kuechler et al., 2015). Although this mutation leads to a premature stop codon, this variant may not cause a complete loss of function protein version due to the mutation location at the end of the protein, which would explain the mild patient’s phenotype. Mutations in the C-terminal region could be associated with weaker phenotype due to a possible escape from the NMD system (nonsense-mediated mRNA decay), that eliminates mRNAs containing premature translation termination codons (Brogna and Wen, 2009; Szczaluba et al., 2016).

In conclusion, we describe a new probably pathogenic variant, as the putative genetic cause of this patient’s motor and cognitive dysfunctions.


We would like to thank the patient and his parents for the help we received in putting this information together.

About the Authors

Corresponding Author

E. Stur

Programa de Pós-Graduação em Biotecno, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo, Vitória, ES, Brazil



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