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).
This gene is predicted to encode a methyltransferase and resides within the critical interval for the 3p25 microdeletion syndrome.
Type of Disorder
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.
Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.
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
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
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.
Cued or contextual fear conditioning: memory of context1
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.
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 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.
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.
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.
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.