A de novo LoF variant and a de novo likely damaging missense variant in the MYT1L gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2017 (PMID 25363760). 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 MYT1L 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. De novo LoF variants in MYT1L were also identified in two sporadic cases in De Rocker et al., 2015: one in a patient presenting with ASD and intellectual disability, and the other in a patient presenting with intellectual disability and autistic features (PMID 25232846). Two additional de novo LoF variants in the MYT1L gene were identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329), and an ASD proband from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). MYT1L has been proposed as a causative gene for intellectual disability and other phenotypes observed in cases with 2p25.3 deletions (PMID 21990140, 25232846). Copy number variants affecting the MYT1L gene have also been implicated in schizophrenia (Vrijenhoek et al., 2008; Lee et al., 2012; Van Den Bossche et al., 2013). A de novo protein-truncating variant in MYT1L was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified MYT1L as a candidate gene with a false discovery rate (FDR) 0.01. Coursimault et al., 2021 described 40 previously unreported cases with pathogenic or likely pathogenic variants in the MYT1L gene; developmental delay, intellectual disability, and behavioral disorders were frequently observed in individuals with MYT1L variants, and a formal or informal diagnosis of autism spectrum disorder was made in 17/40 individuals (43%). 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 MYT1L as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
May function as a panneural transcription factor associated with neuronal differentiation and may play a role in the development of neurons and oligodendroglia in the CNS.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Germline mosaic transmission of a novel duplication of PXDN and MYT1L to two male half-siblings with autism.
Myt1l KO haploinsufficient mice show obesity, white matter thinning, and microcephaly. Behavioral anomalies include hyperactivity, muscle weakness, alteration in social behavior, with more sever phenotypes in males.
References
Type
Title
Author, Year
Primary
A MYT1L syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Crispr-mediated homology-directed repair (hdr) was used to generate myt1l s710fsx mice. founders carrying the appropriate allele were then bred with wild-type mice (jax stock no. 000664). a cas9 grna was designed to target the 7th exon of the mouse myt1l gene (seq: 50 gctcttgctacacgtgctacngg 30), similar to where a patient specific heterozygous de novo mutation defined by our clinical colleagues in a human case with asd (c.2117dupg). validated grna and cas9 protein (idt) were electroporated into fertilized c57bl6/j oocytes along with single stranded oligonucleotides carrying homology to the targeted region and the g mutation as well as blocking oligonucleotides for the other strand to prevent homozygous mutation and presumptive embryonic lethality of founders. f1 pups from the lead founder were genotyped by sequencing, then bred to generate experimental animals.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL6/J
ES Cell Line: Mutant ES Cell Line: Model Source: 34614421
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Crispr-mediated homology-directed repair (hdr) was used to generate myt1l s710fsx mice. founders carrying the appropriate allele were then bred with wild-type mice (jax stock no. 000664). a cas9 grna was designed to target the 7th exon of the mouse myt1l gene (seq: 50 gctcttgctacacgtgctacngg 30), similar to where a patient specific heterozygous de novo mutation defined by our clinical colleagues in a human case with asd (c.2117dupg). validated grna and cas9 protein (idt) were electroporated into fertilized c57bl6/j oocytes along with single stranded oligonucleotides carrying homology to the targeted region and the g mutation as well as blocking oligonucleotides for the other strand to prevent homozygous mutation and presumptive embryonic lethality of founders. f1 pups from the lead founder were genotyped by sequencing, then bred to generate experimental animals.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL6/J
ES Cell Line: Mutant ES Cell Line: Model Source: 34614421
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Zygotes were isolated and electroporated with Cas9 proteins complexed with a guide sequence directed at exon 6, the first coding exon of the Myt1l gene to generate a Myt1l 7 base pair deletion allele and frameshift deletion of Myt1l.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source: Marius Wernig Lab (PMID 35538503)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Zygotes were isolated and electroporated with Cas9 proteins complexed with a guide sequence directed at exon 6, the first coding exon of the Myt1l gene to generate a Myt1l 7 base pair deletion allele and frameshift deletion of Myt1l.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source: Marius Wernig Lab (PMID 35538503)
Description: Hms have decreased apical progenitor (ap, sox2+) density with normal intermediate progenitor (tbr2+) and postmitotic neuron (tbr1+) density compared with het and wt mice; shift from early cell fate (sox2+) to late cell fate (tbr2+/tbr1+) in myt1l mutants
Description: Proliferating cells (ki-67+) were also decreased in hms; both ht and hm cortices have significantly fewer edu+ cells
Exp Paradigm: EdU labeling
Description: Identified 1,522 dars in mutant cortex (ht and hm), with 871 less accessible dars (3a, s3aâ??s3c) and 641 more accessible dars (3b, s3a, s3d, s3e). hm mice showed smaller changes than ht in terms of dars decreasing accessibility after myt1l mutation. myt1l loss decreased the accessibility of binding target regions (figure s3f).
Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq)
Description: Wt 60 s, ht 60 s, hts hung on an inverted screen for a shorter latency than wt mice; adult ht mice hung on an inverted screen for a shorter latency than wt mice
Description: Wt 60 s, ht 51 s, hts exhibited a longer latency than wt mice to climb to the top of a 90 degree screen; ht mice exhibited a longer latency than wt mice to climb to the top of a 90 degree screen
Description: Ht mice traveled farther distances during 1 h social operant trials compared with wt mice; females traveled farther distances than males during social operant trials
Exp Paradigm: adapted standard operant conditioning (8GH) to assess social motivation by rewarding nose pokes with an opportunity for transient social interaction
Description: A subset of ht mice displayed (i) fifth finger clinodactyly and (j and k) abnormal hindlimb posture reflected not in clasping but in holding limb(s) at midline
Description: Significantly smaller brain volume in ht mice
Exp Paradigm: From maps of apparent diffusion coefficient and fractional anisotropy, we segmented several brain regions and performed three-dimensional (3D) reconstruction
Magnetic resonance (MR)-based diffusion tensor imaging (DTI)
Description: Hts had a smaller corpus callosum volume
Exp Paradigm: From maps of apparent diffusion coefficient and fractional anisotropy, we segmented several brain regions and performed three-dimensional (3D) reconstruction
Magnetic resonance (MR)-based diffusion tensor imaging (DTI)
Miniature post synaptic current amplitude: excitatory1
increased
Description: Individual mepsc events were shifted toward larger currents in het neurons (p=0.0063), average mepsc amplitude showed non-significant increase in hets (p=0.13)
Description: Day to reach criteria during social operant training (m) and (n) breakpoint reached during pr3 testing were not different between ht and wt mice; ht males continued to poke despite the presentation of a social reward; ht males tended to spend less time at the door during a reward (8q) and showed a significant decrease in overall time in the interaction zone
Exp Paradigm: adapted standard operant conditioning (8GH) to assess social motivation by rewarding nose pokes with an opportunity for transient social interaction
Description: Ht mice weighed significantly more than wt mice as adults, initial separation of group weights at p45 that became statistically significant at p94 and was more pronounced in females than males
Description: In pfc, 4,988 differentially accessible regions (dars) discovered with 2,607 less accessible dars (5a, s5abc), 2,381 more accessible dars (5b, s5de), and no peak showing a sex by genotype interaction; regions of lost accessibility are enriched for motifs of tfs involved in neuron projection (egr2) and the dd gene foxp1, while those more accessible regions had motifs for an early neuronal tf
Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq)
Description: Identified 1,522 dars in mutant cortex (ht and hm), with 871 less accessible dars (3a, s3aâ??s3c) and 641 more accessible dars (3b, s3a, s3d, s3e). hm mice showed smaller changes than ht in terms of dars decreasing accessibility after myt1l mutation. myt1l loss decreased the accessibility of binding target regions (figure s3f).
Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq)
Description: In pfc, identified 533 of 14,104 degs; genes from early phases of cns development (eomes, dcx) were upregulated in hts; genes downregulated upon myt1l loss were significantly enriched in neuronal genes; downregulation of neuronal projection development (epha7, l1cam), ion homeostasis (kcnt2, kcne4), and synaptic transmission
Description: Myt1l homozygous mutant mice exhibited an increase in the number of Sox2+ cells in the cortex compared to wildtype controls, and no change in the number of Tbr2+ cells.
Exp Paradigm: Sox2, Tbr2
Description: Myt1l homozygous mutant mice exhibited a decreased number of Cdca7+ interneurons and an increased number of cortical layer I neurons (Reln+) compared to wildtype controls.
Description: Myt1l homozygous mutant mice exhibited decreased cortical thickness at two locations of the cortex compared to wildtype controls.
Exp Paradigm: NeuN
Description: Myt1l homozygous mutant mice exhibited a significant decrease in Ki67â??EdU+ cells compared to wildtype controls, as measured by a 37% decrease in the Q fraction.
Exp Paradigm: Ki67
Description: Myt1l homozygous mutant mice exhibited increased rates of postnatal lethality compared to heterozygous and wildtype mice, with none surviving through weaning age.
Description: Neonatal Myt1l homozygous mutant mice appeared normal, but show decreased mendelian ratio at birth, and surviving pups died within 24 h after birth.
Description: In whole brain lysates, homozygotes lack the full-length 170 kDa protein, but show an additional Myt1l band at 158 kDa, as detected separately with two Myt1l antibodies.
Description: Myt1l homozygous mutant mice exhibited global gene upregulation compared to wildtype controls. This upregulation was also more pronounced compared to heterozygous mutant mice.
Description: Myt1l homozygous mutant mice exhibited differentially expressed genes, with distinct clusters of deregulated genes early (E18.5 and P0) in development. At E18.5, there was a downregulation of neurogenesis-associated GO terms and an upregulation of cell division, as well as upregulation of early-fetal gene expression signatures and a decrease of late-fetal signatures.
Description: Myt1l haploinsufficient mice displayed higher distance traveled than wildtype littermates, and this remained during the second exposure.
Exp Paradigm: Low-light (20 lx) activity box, 2 days
Description: Overall motor performance was lower in Myt1l haploinsufficient mice compared to wildtype littermates, irrespective of task difficulty. The genotype difference was particularly prominent on the second day, where the latency to fall was lower in Myt1l haploinsufficient mice than wildtype littermates during all three trials. Genotypes did not differ in the latency to make one complete revolution while hanging on the rotarod, meaning that wildtype littermates were able to remain on the rotarod for longer periods of time and higher number of turns under challenging conditions than Myt1l haploinsufficient mice
Description: Myt1l mutant mice covered more distance in the open arms and displayed an increased number of visits to both the open and closed arms, compared to wildtype control mice.
Description: Myt1l haploinsufficient mice displayed more rearing behavior than wildtype littermates, and this remained during the second exposure.
Exp Paradigm: Low-light (20 lx) activity box, 2 days
Description: Myt1l haploinsufficient mice did not show altered latency to start calling, total time spent calling, and number of ultrasonic vocalizations emitted. Likewise, acoustic features, such as call duration, peak frequency, peak amplitude, and frequency modulation, were not affected. Call emission was non-random, and high temporal organization was evident in both genotypes. However, call clustering was affected by Myt1l haploinsufficiency, and Myt1l haploinsufficient mice pups emitted more ultrasonic vocalizations of the high-frequency (above 70 kHz), but not low-frequency subtype, compared to wildtype littermates.
Description: Myt1l haploinsufficient mice displayed habituation deficit, with weak within-session and between-session habituation during first and second exposure.
Exp Paradigm: Low-light (20 lx) activity box, 2 days
Cued or contextual fear conditioning: Memory of context2
Decreased
Description: Myt1l haploinsufficient mice displayed less freezing behavior than wildtype littermates during contextual recall. Difference was prominent in males.
Exp Paradigm: contextual recall
Description: Myt1l heterozygous mutant mice exhibited an increase in the number of Sox2+ cells in the cortex compared to wildtype controls, and no change in the number of Tbr2+ cells.
Exp Paradigm: Sox2, Tbr2
Description: Myt1l heterozygous mutant mice exhibited decreased cortical thickness at two locations of the cortex compared to wildtype controls.
Exp Paradigm: NeuN
Description: Myt1l heterozygous mutant mice exhibited fewer Tbr2 and Sema3c cell populations, which mark newly-formed migrating neurons in the subventricular zone, compared to wildtype controls.
Spontaneous post synaptic event frequency: inhibitory currents1
Increased
Description: Myt1l mutant mouse hippocampal CA1 pyramidal neurons exhibited an increase in spontaneous inhibitory postsynaptic current frequency in acute brain slices compared to wildtype controls.
Spontaneous post synaptic event frequency: excitatory currents1
Increased
Description: Myt1l mutant mouse hippocampal CA1 pyramidal neurons exhibited an increase in spontaneous excitatory postsynaptic current frequency in acute brain slices compared to wildtype controls.
Description: Myt1l haploinsufficiency led to increased acoustic startle responses; In males, startle reactivity was potentiated in Myt1l haploinsufficient mice during the exposure to pulses with moderate and high sounding intensities of 95, 105, and 115 dB. No differences were seen in response to low sound intensities of 75 and 85 dB.
Description: Myt1l haploinsufficient mice built wider nests than wildtype littermates, which led to higher nest quality in Myt1l haploinsufficient mice. Nest height was not affected by genotype.
Description: Myt1l mutant mice exhibited a decrease in the amount of time spent drinking, and no change in the amount of time spent eating, compared to wildtype control mice.
Description: Myt1l haploinsufficient mice gained more body weight after weaning compared to wildtype littermates, with the weight gain of female haploinsufficient mice being substantially higher than male haploinsufficient mice, and female haploinsufficient mice reaching the same body weight levels as male wildtype littermates. Weight increase significant starting at 18 weeks.
Description: Myt1l haploinsufficiency led to reduced anxiety-related behavior and Myt1l haploinsufficient mice spent more time in the open arms than wildtype littermates. Number of open and closed arm entries did not differ between genotypes, suggesting that the increased time spent in open arms is not a simple reflection of hyperactivity.
Description: Myt1l mutant mice spent less time in the corners and more time in the center, as well as increased distance traveled in the center, compared to wildtype controls.
Description: Myt1l mutant mice spent less time in the corners and more time in the center, as well as increased distance traveled in the center, compared to wildtype controls.
Description: Myt1l mutant mice exhibited an increase in the amount of time spent, distance traveled, and visits in the open arms of the elevated maze, compared to wildtype controls.
Description: Genotype differences emerged with repeated tone-shock pairings and were most prominent toward the end of acquisition. In both sexes, Myt1l heterozygous mice displayed less freezing behavior than wildtype littermate controls.
Exp Paradigm: acquisition
Description: In whole brain lysates, heterozygotes show both the full-length 170 kDa protein, plus an additional Myt1l band at 158 kDa, as detected separately with two Myt1l antibodies. Quantification of 170 kDa band shows a significant decrease in expression level (p=0.02).
Description: Myt1l heterozygous mutant mice exhibited several hundred differentially expressed genes, with distinct clusters of deregulated genes early (E18.5 and P0) and late (P22 and adult) in development. At E18.5, there was a downregulation of neurogenesis-associated GO terms and an upregulation of cell division, as well as upregulation of early-fetal gene expression signatures and a decrease of late-fetal signatures. Additionally, adult mice exhibited a continued down-regulation of neuronal GO terms and an increase in signaling and non-neuronal terms.
