Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%). Two de novo protein-truncating variants in SETD5 were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; additional protein-truncating variants in this gene were observed in case samples from the Danish iPSYCH study in this report. Furthermore, TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified SETD5 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SETD5 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
This gene is predicted to encode a methyltransferase and resides within the critical interval for the 3p25 microdeletion syndrome.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disa...
Setd5 happlodeficient mice show abnormal brain to body weight ratios, neural crest abnormalities, increased LTP, delayed USV, reduced cognitive flexibility, deficits in nest building behavior, and abnormalities in the regulation of gene transcription.
References
Type
Title
Author, Year
Additional
Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
An exchange vector for performing recombinase-mediated cassette exchange was made beginning with pRosa26.Ex1 and inserting a GFP (Emerald)-SV40 poly(A) cassette between SmaI sites located in the first exon of Setd5 resulting in disruption of Setd5 at exon 1.
Allele Type: knockout
Strain of Origin: Genetic Background: CD-1
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: PMID 27864380
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
An exchange vector for performing recombinase-mediated cassette exchange was made beginning with pRosa26.Ex1 and inserting a GFP (Emerald)-SV40 poly(A) cassette between SmaI sites located in the first exon of Setd5 resulting in disruption of Setd5 at exon 1.
Allele Type: knockout
Strain of Origin: Genetic Background: CD-1
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: PMID 27864380
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Setd5 heterozygous mice lacking exons 3 to 6 were generated by mating Setd5^tm1a(EUCOMM)Wtsi mice with Flip mice followed by CMV-Cre mice (CMVCre (B6.C-Tg(CMV-cre)1Cgn/J)
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: International Mouse Phenotyping Consortium, Jackson Laboratories
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with GFP coding sequences inserted in the first exon of Setd5, upstream of the translation initiation sequence, using an RMCE-based strategy resulting in disruption of full-length SetD5 mRNA and protein expression and an effective SetD5^GFP null allele. This is a loss of function knockin.
Allele Type: LOF Knockin
Strain of Origin: C57/Bl6
Genetic Background: C57/Bl6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: PMID 27864380
Cardiovascular development and function: embryonic1
decreased
Description: Staining of cardiac differentiation markers MEF2C and MHC showed abnormal heart development, null embryos showed only weak staining in the anterior heart field and myocardium Similarly, whereas MHC staining of Setd5 het mice showed easily discernible cardiac muscle, and somites and smooth muscle in the dorsal aorta, only the heart region was stained in the null embryos. Hematoxylin and Eosin staining of E9.5 placentas showed that the labyrinthine layer in heterozygous animals was well developed, whereas in knockout placentas this layer was significantly thinner, contained only maternal blood vessels with mature erythrocytes, and embryonic blood vessels remained at the periphery in the chorioallantoic region and did not invade the labyrinthine layer.
Cardiovascular development and function: embryonic1
abnormal
Description: Null embryos had pericrdial effusion, disrupted bloodflow, and only half of had beating hearts at E9.5. Ventricular chambers exhibited reduced trabeculation in the existing single ventricle, a thinner myocardium layer, a large gap between pericardium and myocardium, and no contact between the myocardium and endocardium. Yolk sac was pale with fewer blood vessels which were poorly organized and had an abnormally dialated capillary plexus.
Description: null embryos had fewer somites and some with no closure of the neural tube, defects also included massive pericardial effusion, abnormal formation of caudal structures, tail effusions, disrupted bloodflow and osmotic imbalance
Description: Mutants show increase in early and late field potential recordings compared with controls, indicating abnormal synaptic plasticity.
Exp Paradigm: Ltp of the synaptic transmission at ca3ca1 synapses in hippocampal slices was assayed.
Description: Mutants performed more nose pokes per corner visit even when not seeking water and showed no licks, compared with controls. mutants performed fewer visits to doors with nose pokes but without licks indicating a predisposition for repetitive behavior.
Exp Paradigm: NA
Description: Mutants show displacement in the position of the pupil, corectopia, and dilation of the pupil, mydriasis, compared with controls.
Exp Paradigm: NA
Description: Mutants are viable but are born at a non-mendelian ratio compared with controls. reduced survival is more pronounced in female mutants.
Exp Paradigm: NA
Description: Female mutants show increase in time spent in the open arms but no change in time spent in the closed arms or in number of entries into the open or closed arms compared with controls.
Exp Paradigm: NA
Description: Mutants show decrease in the capacity to extinguish memory of contextual fear as measured by freezing response 24 hours after acquisition of memory, compared with controls.
Exp Paradigm: NA
Description: Mutants show no change in the decrease in the number of visits to the incorrect corner compared with controls, in the beginning of the test. after 24 hours mutants show continued nose pokes at the incorrect and correct corners with comparable frequency whereas controls reduced the number of nose pokes in the incorrect corners, indicating deficiency in adaptive behavior.
Exp Paradigm: Animals get access to water at the four corners of the cage by nose poking on doors. nose poking at other doors yields an aversive air puff.
Description: Mutants show increased capacity to distinguish between old and new location of an object compared with controls that showed no memory trace, 24 hours after a sub-threshold training.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of context1
Increased
Description: Mutants show no change in the acquisition of contextual fear memory compared with controls indicating no change in sensory acuity. female mutants show increased retention of contextual fear memory assessed by increase in freezing response compared with controls, 24 hours after acquisition. males show no increase in freezing response 24 hours after acquisition compared with controls. males do show increase in freezing response 24 hours after acquisition compared to control with weaker training.
Exp Paradigm: NA
Description: Mutants show abnormal expression of genes involved in cells cycle regulation, neurogenesis, eye development, response to bmp and other processes compared with controls. upregulated genes were involved in head and brain development while down-regulated genes were involved in the development of neural crest, heart, limbs and skeleton. aberrant genes also included those involved in eye development such as otx2, aldh1a3, stra6, and sox2.
Exp Paradigm: NA
Description: Mutants show increased acetylation of the lysine 8 of histone 4 in the hippocampus compared with controls. mutants also show increased h4k8 acetylation 3 hours after contextual fear conditioning compared with controls.
Exp Paradigm: NA
Description: Mutants show abnormal expression of wnt signaling pathway components compared with controls, including down regulation of beta catenin and tcf3 target genes.
Exp Paradigm: NA
Description: Mutants show increased expression of activity dependent immediate-early genes fos and egr2 and creb dependent genes 1 hour after conditioning whereas controls show increase of activity dependent immediate-early genes fos and egr2 and creb dependent genes that lasts for 3 hours after conditioning, indicating a difference in transcriptional response to training. genes upregulated in mutants are psd (post synaptic density) genes shank1, camkiin1, cpeb1, fxr2p, and synaptopodin, genes encoding proteins regulating synapse structure and activity, syngap1, lrrc4, and p140cap and genes involved in methylation and acetylation.
Exp Paradigm: NA
Description: Mutants show differences in volumes of multiple brain regions including secondary auditory cortex, dorsolateral orbital cortex and frontal association cortex, when normalized to total brain volume compared with controls.
Exp Paradigm: NA
Description: Mutants show downregulation of zic1, zic4, fgf15, malat1, cadm1, pnoc, kitl, efna5 and nnat genes in the cortex compared with controls.
Exp Paradigm: NA
