{ "title": "ASH1L Evidence Library", "recordCount": 50, "curationRule": "Each record includes a research area, paper-specific primary question, and rationale.", "topicAreaCounts": { "Human disorder": 9, "Molecular function": 11, "Neural systems": 9, "Extra-neural": 9, "Translation": 6, "Methods or context": 6 }, "sourceCoverageThrough": "2026-08-14", "records": [ { "year": "2026", "authors": "Fernandez Garcia M, Retallick-Townsley K, Pruitt A, et al.", "title": "Transcriptomic and phenotypic convergence of neurodevelopmental disorder risk genes in vitro and in vivo", "journal": "Nature Neuroscience", "citation": "29:1079–1094 · doi:10.1038/s41593-026-02247-7", "finding": "A Yale-led study directly perturbed ASH1L within a 23-gene CRISPR program across neural progenitors and glutamatergic and GABAergic neurons, with arrayed ASH1L assays and an ash1l zebrafish model. ASH1L loss increased Ki-67-positive neural progenitors and contributed to cell-state-specific convergence analyses.", "tags": [ "Yale", "CRISPR", "iPSC", "transcriptomics", "zebrafish", "cell type", "mitochondria" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/s41593-026-02247-7" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/42032432/" } ], "doi": "10.1038/s41593-026-02247-7", "pmid": "42032432", "primaryQuestion": "How does ASH1L loss alter proliferation and cell-state programs across neural progenitors, excitatory neurons, inhibitory neurons, and an in vivo zebrafish model?", "primaryQuestionRationale": "The study directly perturbed ASH1L across human neural cell types and zebrafish, finding increased Ki-67-positive neural progenitors while placing broader network results within a 23-gene convergence analysis.", "sourceNumber": 1, "researchArea": "Neural systems", "evidenceCategory": "Functional", "publicationStatus": "Peer reviewed", "interpretationLimit": "This is a gene-knockout study, not a graded ASH1L dosage-response experiment or a functional classification of patient alleles. Most network findings are cross-gene convergence results; the reported Seahorse assay did not identify a significant respiratory change for ASH1L.", "sourceCheckedOn": "2026-07-24" }, { "year": "2026", "authors": "Terceros A, Chen C, Harada Y, et al.", "title": "Thalamocortical transcriptional gates coordinate memory stabilization", "journal": "Nature", "citation": "649:1254–1263 · doi:10.1038/s41586-025-09774-6", "finding": "Targeted perturbation in a mouse memory circuit identified a sequential CAMTA1–TCF4–ASH1L transcriptional cascade. In that task, ASH1L was required later to maintain selected memories over weeks rather than for initial memory formation.", "tags": [ "memory", "stabilization", "thalamus", "cortex", "CRISPR", "mouse" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/s41586-025-09774-6" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/41299170/" } ], "doi": "10.1038/s41586-025-09774-6", "pmid": "41299170", "primaryQuestion": "Is ASH1L required for late stabilization, rather than initial formation, of selected memories in the tested mouse thalamocortical circuit?", "primaryQuestionRationale": "Targeted mouse-circuit perturbation placed ASH1L late in a CAMTA1–TCF4–ASH1L cascade that maintained selected memories over weeks without defining human memory trajectories.", "sourceNumber": 2, "researchArea": "Neural systems", "evidenceCategory": "Models", "publicationStatus": "Peer reviewed", "interpretationLimit": "Circuit- and task-specific mouse evidence. It separates memory stabilization from acquisition experimentally but does not define an individual human memory profile or prove progressive decline.", "sourceCheckedOn": "2026-07-24" }, { "year": "2026", "authors": "Pruitt A, Yang L, Lee S, et al.", "title": "Estradiol modulates neuronal network hyperexcitability in select NDD risk genes", "journal": "bioRxiv", "citation": "2026.02.18.706588 · doi:10.64898/2026.02.18.706588", "finding": "A Yale-led dual-system screen reported ASH1L responses across gene expression and network bursting in human induced neurons and sleep-wake and visual-startle measures in larval zebrafish.", "tags": [ "Yale", "estradiol", "iPSC", "calcium imaging", "zebrafish", "preprint" ], "links": [ { "label": "Preprint", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12934954/" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/41757108/" } ], "doi": "10.64898/2026.02.18.706588", "pmid": "41757108", "primaryQuestion": "Does estradiol alter transcriptional, network-bursting, sleep-wake, or visual-startle phenotypes after ASH1L perturbation in the tested neuronal and zebrafish models?", "primaryQuestionRationale": "This non-peer-reviewed dual-system screen measured ASH1L-linked responses to estradiol in human induced neurons and larval zebrafish but did not test clinical benefit, safety, dose, or timing.", "sourceNumber": 3, "researchArea": "Translation", "evidenceCategory": "Functional", "publicationStatus": "Preprint", "interpretationLimit": "Non-peer-reviewed model-system evidence. It does not establish benefit, safety, dose, timing, or treatment guidance for people with ASH1L-related disorder.", "sourceCheckedOn": "2026-07-24" }, { "year": "2026", "authors": "Jamadagni P, Dai Y, Liu Y, et al.", "title": "Pharmaco-behavioral profiling identifies suppressors of autism gene-associated phenotypes in zebrafish", "journal": "Proceedings of the National Academy of Sciences", "citation": "123(12):e2518846123 · doi:10.1073/pnas.2518846123", "finding": "A Yale-led high-throughput resource profiled 520 FDA-approved drugs across nine large-effect autism-gene zebrafish mutants, extending a cross-gene behavioral and pharmacologic platform relevant to future model-based work.", "tags": [ "Yale", "zebrafish", "drug screen", "behavior", "program context" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1073/pnas.2518846123" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/41838920/" } ], "doi": "10.1073/pnas.2518846123", "pmid": "41838920", "primaryQuestion": "What high-throughput zebrafish pharmacology approach could inform future ASH1L model studies, despite ASH1L not being one of the genes tested?", "primaryQuestionRationale": "The paper profiled 520 approved drugs across nine other autism-gene zebrafish mutants, making it methodological platform context rather than direct ASH1L treatment evidence.", "sourceNumber": 4, "researchArea": "Methods or context", "evidenceCategory": "Functional", "publicationStatus": "Peer reviewed", "interpretationLimit": "ASH1L was not directly tested in this paper. Rescue validation centered on other gene models, so this is Yale platform context—not ASH1L treatment evidence.", "sourceCheckedOn": "2026-07-24" }, { "year": "2025", "authors": "Pruitt A, Gupta AR, Hoffman EJ", "title": "Molecular and genetic mechanisms in autism spectrum disorder", "journal": "Annals of Neurology", "citation": "98(6):1163–1177 · doi:10.1002/ana.70013", "finding": "A Yale review of large-effect autism and NDD mechanisms that places ASH1L among high-confidence chromatin and gene-regulation risk genes.", "tags": [ "Yale", "review", "autism", "chromatin", "mechanism" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1002/ana.70013" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/40801227/" } ], "doi": "10.1002/ana.70013", "pmid": "40801227", "primaryQuestion": "Where does ASH1L fit within the chromatin and gene-regulation mechanisms reviewed for large-effect autism and neurodevelopmental risk genes?", "primaryQuestionRationale": "This broad mechanistic review identifies ASH1L as a high-confidence chromatin and gene-regulation risk gene without supplying ASH1L-specific natural-history, phenotype, or intervention data.", "sourceNumber": 5, "researchArea": "Methods or context", "evidenceCategory": "Synthesis", "publicationStatus": "Peer reviewed", "interpretationLimit": "Contextual synthesis rather than an ASH1L-specific phenotype, natural-history, or intervention study.", "sourceCheckedOn": "2026-07-24" }, { "year": "2023", "authors": "Weinschutz Mendes H, Neelakantan U, Liu Y, et al.", "title": "High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways", "journal": "Cell Reports", "citation": "42(3):112243 · doi:10.1016/j.celrep.2023.112243", "finding": "A Yale-led standardized zebrafish pipeline across ten autism-risk genes, integrating morphology, sleep–wake behavior, sensorimotor response, whole-brain activity, dopaminergic measures, and neuroimmune readouts.", "tags": [ "Yale", "zebrafish", "neuroimmune", "dopamine", "sleep", "whole brain" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1016/j.celrep.2023.112243" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/36933215/" } ], "doi": "10.1016/j.celrep.2023.112243", "pmid": "36933215", "primaryQuestion": "How can a standardized multi-domain zebrafish pipeline be used to test convergence across autism-risk genes in future ASH1L work?", "primaryQuestionRationale": "The study integrated morphology, behavior, brain activity, dopamine, and neuroimmune readouts across ten genes that did not include ASH1L, so its relevance is methodological only.", "sourceNumber": 6, "researchArea": "Methods or context", "evidenceCategory": "Functional", "publicationStatus": "Peer reviewed", "interpretationLimit": "ASH1L was not one of the ten genes tested. This paper is included only as methodological context for the later Yale program and must not be cited as direct ASH1L evidence.", "sourceCheckedOn": "2026-07-24" }, { "year": "2025", "authors": "Pulatov O, Nguyen W, Alvarez Vega D, Barros R", "title": "A novel de novo missense variant in ASH1L associated with mild autism spectrum disorder and an uneven cognitive profile: a case report", "journal": "Journal of Medical Case Reports", "citation": "19:616 · doi:10.1186/s13256-025-05675-4", "finding": "Reports a de novo missense variant with mild autism and an uneven neuropsychological profile, including relative verbal strengths.", "tags": [ "human", "missense", "VUS", "autism", "cognition" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12649092/" }, { "label": "DOI", "href": "https://doi.org/10.1186/s13256-025-05675-4" } ], "doi": "10.1186/s13256-025-05675-4", "pmid": "41291913", "primaryQuestion": "What autism and neuropsychological features were reported in the individual with a de novo ASH1L missense variant, and how certain was the variant interpretation?", "primaryQuestionRationale": "The single case described mild autism and an uneven cognitive profile with relative verbal strengths, while the missense variant remained a VUS and therefore could not establish causality.", "sourceNumber": 7, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "Single case; the variant remained a VUS and cannot define pathogenicity or a missense-class severity rule.", "sourceCheckedOn": "2026-07-24" }, { "year": "2025", "authors": "Liao B, Xie W, He S", "title": "Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability", "journal": "Frontiers in Neurology", "citation": "16:1524532 · doi:10.3389/fneur.2025.1524532", "finding": "Adds a truncating case with comparatively mild reported intellectual disability and reviews previously reported nonsense variants.", "tags": [ "human", "nonsense", "intellectual disability", "variant review" ], "links": [ { "label": "Full text", "href": "https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1524532/full" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/39902220/" } ], "doi": "10.3389/fneur.2025.1524532", "pmid": "39902220", "primaryQuestion": "What phenotype was reported with the novel heterozygous ASH1L nonsense variant, and does that case support a position-based severity rule?", "primaryQuestionRationale": "The report added one comparatively mild intellectual-disability case and reviewed prior nonsense variants, but its case-report design cannot establish a deterministic relationship between truncation position and severity.", "sourceNumber": 8, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "Case-report and literature-review evidence; it does not establish a deterministic truncation-position or severity relationship.", "sourceCheckedOn": "2026-07-24" }, { "year": "2025", "authors": "Papendorp C, Nolan E, Higashimori H, et al.", "title": "Mutations in ASH1L cause a neurodevelopmental disorder with sex differences in epilepsy and autism", "journal": "bioRxiv", "citation": "2025.02.21.639570 · doi:10.1101/2025.02.21.639570", "finding": "Combines clinical phenotyping with two mouse backgrounds, neuronal morphology, seizures, and electrophysiology; reports sex-associated differences in its human and mouse datasets.", "tags": [ "preprint", "sex", "epilepsy", "autism", "mouse", "electrophysiology" ], "links": [ { "label": "Preprint", "href": "https://www.biorxiv.org/content/10.1101/2025.02.21.639570" } ], "doi": "10.1101/2025.02.21.639570", "pmid": null, "primaryQuestion": "Do the ascertained human and mouse datasets in this preprint suggest sex-associated differences in epilepsy or autism-related phenotypes after ASH1L disruption?", "primaryQuestionRationale": "The preprint combined limited clinical observations with two mouse backgrounds, neuronal morphology, seizures, and electrophysiology, allowing exploratory sex-associated comparisons but not population-level penetrance estimates.", "sourceNumber": 9, "researchArea": "Neural systems", "evidenceCategory": "Models", "publicationStatus": "Preprint", "interpretationLimit": "Preprint with limited and ascertained human data. It does not establish population-level sex-specific penetrance or prognosis.", "sourceCheckedOn": "2026-07-24" }, { "year": "2025", "authors": "Toolan KP, McGrath BT, Brinkmeier ML, et al.", "title": "Ash1l loss-of-function results in structural birth defects and altered cortical development", "journal": "Brain", "citation": "148(1):55–68 · doi:10.1093/brain/awae218", "finding": "Germline and cortical-lineage mouse models show structural birth defects, altered progenitor balance, and cortical-neuron-fate effects.", "tags": [ "mouse", "cortical development", "birth defects", "SATB2" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11706301/" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/38943682/" } ], "doi": "10.1093/brain/awae218", "pmid": "38943682", "primaryQuestion": "How does Ash1l loss affect structural development, cortical progenitor balance, and neuronal fate in the tested mouse models?", "primaryQuestionRationale": "Germline and cortical-lineage mouse perturbations produced structural birth defects and altered cortical development, findings that do not directly predict outcomes in human heterozygous disorder.", "sourceNumber": 10, "researchArea": "Neural systems", "evidenceCategory": "Models", "publicationStatus": "Peer reviewed", "interpretationLimit": "Developmental mouse findings, including homozygous outcomes, do not predict the course of human heterozygous ASH1L-related disorder.", "sourceCheckedOn": "2026-07-24" }, { "year": "2025", "authors": "Vann KR, Sharma R, Hsu C-C, et al.", "title": "Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation", "journal": "Nature Communications", "citation": "16:2235 · doi:10.1038/s41467-025-57556-5", "finding": "Refines the catalytic and reader-domain architecture of ASH1L, including H3K4me3 engagement and locus-specific chromatin regulation.", "tags": [ "structure", "H3K36", "H3K4", "PHD", "BAH" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/s41467-025-57556-5" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/40044670/" } ], "doi": "10.1038/s41467-025-57556-5", "pmid": "40044670", "primaryQuestion": "How do ASH1L catalytic and reader-domain features support recognition of methylated histone H3 and locus-specific chromatin regulation?", "primaryQuestionRationale": "The study refines ASH1L domain architecture and H3K4me3 engagement in chromatin regulation without showing that protein position alone predicts clinical severity or treatment response.", "sourceNumber": 11, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Structure-function evidence does not convert protein position alone into a clinical-severity or treatment prediction.", "sourceCheckedOn": "2026-07-24" }, { "year": "2024", "authors": "Cordova I, Blesson A, Savatt JM, et al.", "title": "Expansion of the genotypic and phenotypic spectrum of ASH1L-related syndromic neurodevelopmental disorder", "journal": "Genes", "citation": "15(4):423 · doi:10.3390/genes15040423", "finding": "A focused cohort expanding the published human phenotype and molecular spectrum, with feature-specific denominators.", "tags": [ "human", "cohort", "phenotype", "loss of function", "missense" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11049257/" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/38674358/" } ], "doi": "10.3390/genes15040423", "pmid": "38674358", "primaryQuestion": "Which molecular findings and clinical features broaden the reported spectrum of ASH1L-related syndromic neurodevelopmental disorder in this cohort?", "primaryQuestionRationale": "This retrospective focused cohort contributes feature-specific denominators and expands the published molecular and phenotypic spectrum, but its cohort cannot stand in for the connected 63-person dataset or population prevalence.", "sourceNumber": 12, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "Retrospective published cohort; its denominators cannot be substituted for the connected 63-person dataset or a population estimate.", "sourceCheckedOn": "2026-07-24" }, { "year": "2024", "authors": "Jhanji M, et al.", "title": "Dynamic regulation of the chromatin environment by ASH1L modulates human neuronal structure and function", "journal": "bioRxiv", "citation": "2024.12.02.625500 · doi:10.1101/2024.12.02.625500", "finding": "Uses ASH1L-variant human iPSC-derived neurons to examine chromatin, transcription, splicing, morphology, and in-vitro pharmacologic rescue of neurite phenotypes.", "tags": [ "preprint", "iPSC", "human neurons", "chromatin", "splicing", "neurite" ], "links": [ { "label": "Preprint", "href": "https://www.biorxiv.org/content/10.1101/2024.12.02.625500" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/39677608/" } ], "doi": "10.1101/2024.12.02.625500", "pmid": "39677608", "primaryQuestion": "How do ASH1L variants alter chromatin, transcription, splicing, morphology, and function in human iPSC-derived neurons, and can neurite phenotypes be rescued in vitro?", "primaryQuestionRationale": "The preprint studies ASH1L-variant human neurons and reports cultured-cell pharmacologic rescue of neurite phenotypes, which remains preclinical evidence rather than treatment guidance.", "sourceNumber": 13, "researchArea": "Translation", "evidenceCategory": "Functional", "publicationStatus": "Preprint", "interpretationLimit": "Preprint and in-vitro evidence. Tazemetostat or vorinostat rescue in cultured neurons is not clinical treatment evidence.", "sourceCheckedOn": "2026-07-24" }, { "year": "2024", "authors": "Ma K, et al.", "title": "Chemogenetic inhibition of prefrontal cortex ameliorates autism-like social deficits and absence-like seizures in a gene-trap Ash1l haploinsufficiency mouse model", "journal": "Genes", "citation": "15(12):1619 · doi:10.3390/genes15121619", "finding": "Links prefrontal-cortex hyperexcitability to social and seizure-related phenotypes in a mouse model and tests circuit-level chemogenetic suppression.", "tags": [ "mouse", "prefrontal cortex", "chemogenetics", "seizure", "hyperexcitability" ], "links": [ { "label": "Full text", "href": "https://www.mdpi.com/2073-4425/15/12/1619" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/39766886/" } ], "doi": "10.3390/genes15121619", "pmid": "39766886", "primaryQuestion": "Does chemogenetic inhibition of prefrontal cortex reduce social deficits and absence-like seizures in the tested Ash1l haploinsufficiency mouse model?", "primaryQuestionRationale": "The mouse experiment links prefrontal hyperexcitability to behavioral and seizure-related phenotypes and tests circuit suppression without establishing a human therapy or universal mechanism.", "sourceNumber": 14, "researchArea": "Translation", "evidenceCategory": "Models", "publicationStatus": "Peer reviewed", "interpretationLimit": "Circuit intervention in mice is not evidence for a human therapy or for a single cortical mechanism across ASH1L variants.", "sourceCheckedOn": "2026-07-24" }, { "year": "2024", "authors": "Zhao X, Lin S, Ren H, et al.", "title": "The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis", "journal": "Cell Death & Differentiation", "citation": "31(5):605–617 · doi:10.1038/s41418-024-01274-w", "finding": "Defines an ASH1L-dependent osteoclast differentiation and bone-resorption mechanism in the tested systems.", "tags": [ "bone", "osteoclast", "extra-neural", "mouse" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/38431690/" }, { "label": "DOI", "href": "https://doi.org/10.1038/s41418-024-01274-w" } ], "doi": "10.1038/s41418-024-01274-w", "pmid": "38431690", "primaryQuestion": "How does ASH1L regulate osteoclast differentiation and bone resorption in the tested bone-loss systems?", "primaryQuestionRationale": "The study identifies an ASH1L-dependent osteoclastogenesis mechanism that motivates bone-focused measurement but does not attribute any individual skeletal finding to ASH1L.", "sourceNumber": 15, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "Biological rationale for bone-focused measurement, not evidence that an individual skeletal finding is ASH1L-mediated.", "sourceCheckedOn": "2026-07-24" }, { "year": "2024", "authors": "Du X, et al.", "title": "Ash1L ameliorates psoriasis via limiting neuronal activity-dependent release of miR-let-7b", "journal": "British Journal of Pharmacology", "citation": "181(7):1107–1127 · doi:10.1111/bph.16254", "finding": "Connects neuronal Ash1l, activity-dependent let-7b release, and cutaneous inflammatory signaling in a psoriasis model.", "tags": [ "skin", "neuron", "inflammation", "let-7b", "psoriasis" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1111/bph.16254" } ], "doi": "10.1111/bph.16254", "pmid": "37766518", "primaryQuestion": "Does neuronal Ash1l limit psoriasis-like inflammation by regulating activity-dependent release of miR-let-7b in the tested model?", "primaryQuestionRationale": "This disease-specific animal study connects neuronal Ash1l, let-7b release, and cutaneous inflammatory signaling without establishing psoriasis or a shared neurocutaneous mechanism in ASH1L-related neurodevelopmental disorder.", "sourceNumber": 16, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "Disease-specific animal work; it does not establish psoriasis or a shared neurocutaneous mechanism in ASH1L-related NDD.", "sourceCheckedOn": "2026-07-24" }, { "year": "2023", "authors": "Yoon E, Song JJ", "title": "Caf1 regulates the histone methyltransferase activity of Ash1 by sensing unmodified histone H3", "journal": "Epigenetics & Chromatin", "citation": "16:15 · doi:10.1186/s13072-023-00487-6", "finding": "Biochemical work showed that Caf1 binds the Ash1 complex near its reader-domain region, senses unmodified H3K4, and regulates H3K36 methyltransferase activity.", "tags": [ "Caf1", "RBBP4", "H3K4", "H3K36", "structure" ], "links": [ { "label": "Full text", "href": "https://link.springer.com/article/10.1186/s13072-023-00487-6" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/37118845/" } ], "doi": "10.1186/s13072-023-00487-6", "pmid": "37118845", "primaryQuestion": "How does Caf1 sensing of unmodified histone H3 regulate the H3K36 methyltransferase activity of the Ash1 complex?", "primaryQuestionRationale": "Biochemical experiments place Caf1 near the Ash1 reader-domain region and show regulation through H3K4-state sensing, without testing human variants, dosage, neurodevelopment, or treatment response.", "sourceNumber": 17, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Mechanistic protein-complex and chromatin evidence. It does not test human ASH1L variants, neurodevelopmental phenotypes, gene dosage, or treatment response.", "sourceCheckedOn": "2026-07-24" }, { "year": "2023", "authors": "Al-Harthi S, Li H, Winkler A, et al.", "title": "MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes", "journal": "Structure", "citation": "31(10):1200–1207.e5 · doi:10.1016/j.str.2023.07.001", "finding": "Tests how full-length MRG15 enhances ASH1L nucleosome engagement and catalytic activity.", "tags": [ "MRG15", "nucleosome", "structure", "H3K36" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/37527654/" }, { "label": "DOI", "href": "https://doi.org/10.1016/j.str.2023.07.001" } ], "doi": "10.1016/j.str.2023.07.001", "pmid": "37527654", "primaryQuestion": "How does full-length MRG15 recruit ASH1L to nucleosomes and enhance its methyltransferase activity?", "primaryQuestionRationale": "The study tests MRG15-dependent nucleosome engagement and catalytic activation of ASH1L as a protein-complex mechanism, not patient-specific MRG15 dysfunction or clinical phenotype.", "sourceNumber": 18, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Protein-complex mechanism does not establish patient-specific MRG15 dysfunction or clinical phenotype.", "sourceCheckedOn": "2026-07-24" }, { "year": "2023", "authors": "Maritz C, Khaleghi R, Yancoskie MN, et al.", "title": "ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair", "journal": "Nature Communications", "citation": "14:3892 · doi:10.1038/s41467-023-39635-7", "finding": "In cultured human cells exposed to UV, ASH1L and MRG15 supported lesion-associated H3K4me3, XPC redistribution, downstream repair-factor engagement, and FACT recruitment in global-genome nucleotide-excision repair.", "tags": [ "MRG15", "H3K4me3", "FACT", "XPC", "UV", "nucleotide excision repair" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/s41467-023-39635-7" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/37393406/" } ], "doi": "10.1038/s41467-023-39635-7", "pmid": "37393406", "primaryQuestion": "How do ASH1L and MRG15 support lesion verification and global-genome nucleotide-excision repair after UV exposure in cultured human cells?", "primaryQuestionRationale": "The cultured-cell study links ASH1L–MRG15 to lesion-associated H3K4me3, XPC redistribution, repair-factor engagement, and FACT recruitment without establishing a clinical DNA-repair disorder or screening indication.", "sourceNumber": 19, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "This is a defined cultured-cell UV-repair context. It does not establish a generalized DNA-repair disorder, genome instability, UV sensitivity, or a clinical screening indication in people with ASH1L-related neurodevelopmental disorder.", "sourceCheckedOn": "2026-07-24" }, { "year": "2023", "authors": "Zhu JY, Liu C, Huang X, et al.", "title": "H3K36 Di-Methylation Marks, Mediated by Ash1 in Complex with Caf1-55 and MRG15, Are Required during Drosophila Heart Development", "journal": "Journal of Cardiovascular Development and Disease", "citation": "10(7):307 · doi:10.3390/jcdd10070307", "finding": "In Drosophila, Ash1-dependent H3K36me2 and its Caf1-55 and MRG15 complex partners were required for normal cardiac development and function.", "tags": [ "heart", "cardiac development", "Drosophila", "H3K36", "MRG15", "Caf1-55" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10380788/" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/37504562/" } ], "doi": "10.3390/jcdd10070307", "pmid": "37504562", "primaryQuestion": "Are Ash1-dependent H3K36me2 and its Caf1-55 and MRG15 complex partners required for normal heart development and function in Drosophila?", "primaryQuestionRationale": "The fly study supports a cardiac-development mechanism involving the Ash1 ortholog and its complex partners but cannot establish human cardiac manifestations or screening needs.", "sourceNumber": 20, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "Distal species evidence involving the fly Ash1 ortholog. It supports a developmental tissue mechanism but does not establish a human cardiac phenotype or screening indication.", "sourceCheckedOn": "2026-07-24" }, { "year": "2022", "authors": "Yan Y, Tian M, Li M, et al.", "title": "ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder", "journal": "Neuron", "citation": "110(7):1156–1172.e9 · doi:10.1016/j.neuron.2021.12.035", "finding": "Connects Ash1l haploinsufficiency to developmental and behavioral phenotypes and implicates EphA7-dependent synaptic refinement in mice.", "tags": [ "mouse", "EphA7", "synapse", "haploinsufficiency" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/35081333/" }, { "label": "DOI", "href": "https://doi.org/10.1016/j.neuron.2021.12.035" } ], "doi": "10.1016/j.neuron.2021.12.035", "pmid": "35081333", "primaryQuestion": "Does Ash1l haploinsufficiency disrupt EphA7-dependent synaptic refinement in association with autism-like phenotypes in mice?", "primaryQuestionRationale": "The mouse study connects Ash1l haploinsufficiency, developmental and behavioral phenotypes, and an EphA7-linked synaptic pathway without validating a human biomarker or treatment target.", "sourceNumber": 21, "researchArea": "Neural systems", "evidenceCategory": "Models", "publicationStatus": "Peer reviewed", "interpretationLimit": "Model-supported pathway, not a validated human biomarker or treatment target.", "sourceCheckedOn": "2026-07-24" }, { "year": "2022", "authors": "Gao Y, Aljazi MB, He J", "title": "Neural hyperactivity is a core pathophysiological change induced by deletion of an autism risk gene Ash1l in the mouse brain", "journal": "Frontiers in Behavioral Neuroscience", "citation": "16:873466 · doi:10.3389/fnbeh.2022.873466", "finding": "He Lab work reports locomotor and metabolic hyperactivity, disturbed sleep, lower induced-seizure threshold, and increased regional neuronal activity in Ash1l-deficient mice.", "tags": [ "He Lab", "MSU", "mouse", "sleep", "seizure", "hyperactivity" ], "links": [ { "label": "Full text", "href": "https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2022.873466/full" } ], "doi": "10.3389/fnbeh.2022.873466", "pmid": "35449559", "primaryQuestion": "Does Ash1l deletion produce neural hyperactivity alongside altered sleep, metabolism, locomotion, and seizure threshold in mice?", "primaryQuestionRationale": "The study reports increased regional neuronal activity with behavioral and physiological changes in Ash1l-deficient mice, which does not establish the same state mechanism or endpoint in people.", "sourceNumber": 22, "researchArea": "Neural systems", "evidenceCategory": "Models", "publicationStatus": "Peer reviewed", "interpretationLimit": "Mouse behavioral and physiological phenotypes do not establish a corresponding human state mechanism or clinical endpoint.", "sourceCheckedOn": "2026-07-24" }, { "year": "2022", "authors": "Zhang T, Ren T, Lin H, et al.", "title": "ASH1L contributes to oocyte apoptosis by regulating DNA damage", "journal": "American Journal of Physiology–Cell Physiology", "citation": "323(4):C1264–C1273 · doi:10.1152/ajpcell.00196.2022", "finding": "Ash1l overexpression in mouse fetal ovaries altered DNA double-strand-break repair signaling and increased oocyte apoptosis in the tested system.", "tags": [ "ovary", "oocyte", "DNA damage", "overexpression", "mouse", "dosage direction" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9576165/" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/36094439/" } ], "doi": "10.1152/ajpcell.00196.2022", "pmid": "36094439", "primaryQuestion": "Does Ash1l overexpression alter DNA-damage signaling and oocyte survival in mouse fetal ovaries?", "primaryQuestionRationale": "The experiment links Ash1l overexpression to altered double-strand-break repair signaling and increased oocyte apoptosis, a perturbation direction that cannot establish fertility risk from ASH1L haploinsufficiency.", "sourceNumber": 23, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "This is an overexpression experiment—the opposite perturbation direction from haploinsufficiency—and does not establish fertility risk in people with ASH1L-related disorder.", "sourceCheckedOn": "2026-07-24" }, { "year": "2022", "authors": "Yu M, Jia Y, Ma Z, et al.", "title": "Structural insight into ASH1L PHD finger recognizing methylated histone H3K4 and promoting cell growth in prostate cancer", "journal": "Frontiers in Oncology", "citation": "12:906807 · doi:10.3389/fonc.2022.906807", "finding": "Provides structural information about the PHD finger and histone-tail recognition.", "tags": [ "PHD", "H3K4", "structure", "cancer" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9399681/" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/36033518/" } ], "doi": "10.3389/fonc.2022.906807", "pmid": "36033518", "primaryQuestion": "How does the ASH1L PHD finger recognize methylated histone H3K4 in the studied prostate-cancer context?", "primaryQuestionRationale": "The structural work characterizes PHD-finger recognition of histone tails and associated cell growth in cancer without supporting a clinical inference for ASH1L-related neurodevelopmental disorder.", "sourceNumber": 24, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Cancer context; it does not support a clinical inference for ASH1L-related neurodevelopmental disorder.", "sourceCheckedOn": "2026-07-24" }, { "year": "2022", "authors": "Liu S, et al.", "title": "ASH1L may contribute to risk of Tourette syndrome: combination of family-based analysis and case-control study", "journal": "Brain and Behavior", "citation": "12(4):e2539 · doi:10.1002/brb3.2539", "finding": "Examines common-variant association with Tourette syndrome using family-based and case-control analyses.", "tags": [ "human", "Tourette", "association", "common variant" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9014991/" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/35307981/" } ], "doi": "10.1002/brb3.2539", "pmid": "35307981", "primaryQuestion": "Do family-based and case-control analyses support an association between common ASH1L variants and Tourette syndrome?", "primaryQuestionRationale": "The paper reports family transmission alongside a nonsignificant case-control result for common-variant risk, which must remain separate from rare pathogenic ASH1L loss-of-function disorder.", "sourceNumber": 25, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "The family transmission result and nonsignificant case-control result concern common-variant risk and must not be conflated with rare pathogenic ASH1L loss-of-function disorder.", "sourceCheckedOn": "2026-07-24" }, { "year": "2021", "authors": "Cheon Y, et al.", "title": "Overcoming the effect of ASH1L haploinsufficiency on stem cells amenability to genome editing and differentiation into neuronal lineage", "journal": "bioRxiv", "citation": "2021.09.27.461943 · doi:10.1101/2021.09.27.461943", "finding": "Technical report on genome editing and neuronal differentiation challenges in ASH1L-haploinsufficient stem-cell systems.", "tags": [ "preprint", "stem cell", "genome editing", "neuronal differentiation" ], "links": [ { "label": "Preprint", "href": "https://www.biorxiv.org/content/10.1101/2021.09.27.461943" } ], "doi": "10.1101/2021.09.27.461943", "pmid": null, "primaryQuestion": "What laboratory barriers does ASH1L haploinsufficiency create for genome editing of stem cells and their differentiation into a neuronal lineage?", "primaryQuestionRationale": "This preprint defines model-generation and neuronal-differentiation constraints in ASH1L-haploinsufficient stem cells, not evidence of a human treatment effect.", "sourceNumber": 26, "researchArea": "Translation", "evidenceCategory": "Functional", "publicationStatus": "Preprint", "interpretationLimit": "Preprint focused on model generation and laboratory workflow, not human phenotype or treatment.", "sourceCheckedOn": "2026-07-24" }, { "year": "2021", "authors": "Gao Y, Duque-Wilckens N, Aljazi MB, et al.", "title": "Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors", "journal": "Communications Biology", "citation": "4:756 · doi:10.1038/s42003-021-02282-z", "finding": "He Lab developmental neural-lineage deletion supports effects on cortical development, myelination, cognition, and behavior.", "tags": [ "He Lab", "MSU", "mouse", "cortex", "myelination", "development" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/s42003-021-02282-z" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/34145365/" } ], "doi": "10.1038/s42003-021-02282-z", "pmid": "34145365", "primaryQuestion": "How does developmental neural-lineage loss of Ash1l affect cortical development, myelination, cognition, and behavior in mice?", "primaryQuestionRationale": "The neural-lineage mouse deletion links Ash1l loss to several developmental brain and behavioral outcomes, while its broad Nestin-lineage design cannot assign them to one cell class or to humans.", "sourceNumber": 27, "researchArea": "Neural systems", "evidenceCategory": "Models", "publicationStatus": "Peer reviewed", "interpretationLimit": "Nestin-lineage mouse deletion includes multiple neural cell classes and does not isolate a mature astrocyte, microglial, or human mechanism.", "sourceCheckedOn": "2026-07-24" }, { "year": "2021", "authors": "Qin L, Williams JB, Tan T, et al.", "title": "Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures", "journal": "Nature Communications", "citation": "12:6589 · doi:10.1038/s41467-021-26972-8", "finding": "Region-specific mouse work links Ash1l deficiency to altered transcription, neuronal hyperactivity, excitation/inhibition imbalance, and seizures.", "tags": [ "mouse", "prefrontal cortex", "seizure", "E/I balance", "epigenetic" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8593046/" }, { "label": "DOI", "href": "https://doi.org/10.1038/s41467-021-26972-8" } ], "doi": "10.1038/s41467-021-26972-8", "pmid": "34782621", "primaryQuestion": "How does Ash1l deficiency in the prefrontal cortex alter transcription, neuronal excitability, excitation-inhibition balance, and seizure susceptibility in mice?", "primaryQuestionRationale": "The regional mouse perturbation tests a plausible route from Ash1l deficiency to hyperactivity and seizures but does not define all contributing cell types or human seizure trajectories.", "sourceNumber": 28, "researchArea": "Neural systems", "evidenceCategory": "Models", "publicationStatus": "Peer reviewed", "interpretationLimit": "Regional perturbation does not define all cell types, clinical variants, or human seizure trajectories.", "sourceCheckedOn": "2026-07-24" }, { "year": "2021", "authors": "Wu Y, Gao Y, Aljazi MB, He J", "title": "Vorinostat, a histone deacetylase inhibitor, ameliorates sociability and cognitive memory in an Ash1L-deletion-induced ASD/ID mouse model", "journal": "Neuroscience Letters", "citation": "759:136016 · doi:10.1016/j.neulet.2021.136016", "finding": "He Lab mouse study reports postnatal vorinostat-associated improvement in selected social and memory measures.", "tags": [ "He Lab", "MSU", "mouse", "vorinostat", "HDAC inhibitor", "rescue" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/34509565/" }, { "label": "DOI", "href": "https://doi.org/10.1016/j.neulet.2021.136016" } ], "doi": "10.1016/j.neulet.2021.136016", "pmid": "34509565", "primaryQuestion": "Can postnatal vorinostat improve selected sociability and cognitive-memory measures in an Ash1l-deletion mouse model?", "primaryQuestionRationale": "The reported rescue is limited to selected outcomes in a mouse model and does not establish vorinostat efficacy, safety, timing, or clinical use in people.", "sourceNumber": 29, "researchArea": "Translation", "evidenceCategory": "Models", "publicationStatus": "Peer reviewed", "interpretationLimit": "Preclinical mouse pharmacology. It does not establish human efficacy, safety, timing, or clinical use of vorinostat.", "sourceCheckedOn": "2026-07-24" }, { "year": "2021", "authors": "Rogawski DS, et al.", "title": "Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity", "journal": "Nature Communications", "citation": "12:2792 · doi:10.1038/s41467-021-23152-6", "finding": "Develops chemical probes that inhibit ASH1L catalytic activity in leukemia models.", "tags": [ "inhibitor", "chemical probe", "leukemia", "SET domain" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/s41467-021-23152-6" }, { "label": "DOI", "href": "https://doi.org/10.1038/s41467-021-23152-6" } ], "doi": "10.1038/s41467-021-23152-6", "pmid": "33990599", "primaryQuestion": "Can first-in-class chemical probes inhibit ASH1L catalytic activity and produce anti-leukemic effects in leukemia models?", "primaryQuestionRationale": "The study establishes catalytic inhibition in leukemia models, a direction that does not supply a treatment rationale for an ASH1L reduced-dosage neurodevelopmental disorder.", "sourceNumber": 30, "researchArea": "Translation", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "ASH1L-related NDD is primarily a reduced-dosage disorder; an ASH1L inhibitor is not a therapeutic rationale for haploinsufficiency.", "sourceCheckedOn": "2026-07-24" }, { "year": "2021", "authors": "Zhang C, et al.", "title": "Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders", "journal": "Developmental Neurobiology", "citation": "81(2):79–91 · doi:10.1002/dneu.22795", "finding": "Reviews ASH1L genetics and model biology across Tourette syndrome, autism, and intellectual disability.", "tags": [ "review", "Tourette", "autism", "neurodevelopment" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8048680/" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/33258273/" } ], "doi": "10.1002/dneu.22795", "pmid": "33258273", "primaryQuestion": "How do ASH1L genetics and model findings relate across Tourette syndrome, autism, and intellectual disability?", "primaryQuestionRationale": "This narrative review compares ASH1L evidence across several neurodevelopmental contexts without establishing that their ascertainment, mechanisms, or clinical phenotypes are interchangeable.", "sourceNumber": 31, "researchArea": "Methods or context", "evidenceCategory": "Synthesis", "publicationStatus": "Peer reviewed", "interpretationLimit": "Narrative synthesis; disease contexts and variant mechanisms should not be merged into one clinical phenotype.", "sourceCheckedOn": "2026-07-24" }, { "year": "2021", "authors": "Liu H, Liu D-T, Lan S, et al.", "title": "ASH1L mutation caused seizures and intellectual disability in twin sisters", "journal": "Journal of Clinical Neuroscience", "citation": "91:69–74 · doi:10.1016/j.jocn.2021.06.038", "finding": "Twin report relevant to epilepsy, inheritance, and within-family phenotypic comparison.", "tags": [ "human", "twins", "epilepsy", "familial" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/34373061/" }, { "label": "DOI", "href": "https://doi.org/10.1016/j.jocn.2021.06.038" } ], "doi": "10.1016/j.jocn.2021.06.038", "pmid": "34373061", "primaryQuestion": "What do ASH1L-associated seizures and intellectual disability in twin sisters show about inheritance and within-family phenotypic comparison?", "primaryQuestionRationale": "The twin report supports a within-family clinical comparison, but the related individuals are not independent recurrence events and cannot establish penetrance.", "sourceNumber": 32, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "Related individuals are not independent recurrence events and cannot establish penetrance.", "sourceCheckedOn": "2026-07-24" }, { "year": "2020", "authors": "Liu S, Tian M, He F, et al.", "title": "Mutations in ASH1L confer susceptibility to Tourette syndrome", "journal": "Molecular Psychiatry", "citation": "25(2):476–490 · doi:10.1038/s41380-019-0560-8", "finding": "Human genetic analysis with functional and animal-model follow-up supporting ASH1L as a Tourette-susceptibility gene.", "tags": [ "human", "Tourette", "genetics", "model" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/31673123/" }, { "label": "DOI", "href": "https://doi.org/10.1038/s41380-019-0560-8" } ], "doi": "10.1038/s41380-019-0560-8", "pmid": "31673123", "primaryQuestion": "Do human genetic and functional data support ASH1L as a susceptibility gene for Tourette syndrome?", "primaryQuestionRationale": "The study addresses Tourette-syndrome susceptibility using human and follow-up model evidence, an ascertainment context distinct from ASH1L haploinsufficiency-related neurodevelopmental disorder.", "sourceNumber": 33, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "Tourette-susceptibility findings are a distinct ascertainment and disease context from ASH1L haploinsufficiency-related NDD.", "sourceCheckedOn": "2026-07-24" }, { "year": "2019", "authors": "Shen W, Krautscheid P, Rutz AM, et al.", "title": "De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental disorder", "journal": "European Journal of Medical Genetics", "citation": "62(1):55–60 · doi:10.1016/j.ejmg.2018.05.003", "finding": "Foundational focused human series supporting de novo loss-of-function as a disease mechanism.", "tags": [ "human", "loss of function", "de novo", "foundational" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/29753921/" }, { "label": "DOI", "href": "https://doi.org/10.1016/j.ejmg.2018.05.003" } ], "doi": "10.1016/j.ejmg.2018.05.003", "pmid": "29753921", "primaryQuestion": "Do de novo loss-of-function variants in ASH1L define an emerging neurodevelopmental disorder?", "primaryQuestionRationale": "This focused early series supports de novo loss of function as a disease mechanism but is too small to define the full phenotype, natural history, or feature frequencies.", "sourceNumber": 34, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "Small early series; it does not define the full phenotype, natural history, or prevalence of individual features.", "sourceCheckedOn": "2026-07-24" }, { "year": "2019", "authors": "Lee Y, Yoon E, Cho S, et al.", "title": "Structural Basis of MRG15-Mediated Activation of the ASH1L Histone Methyltransferase by Releasing an Autoinhibitory Loop", "journal": "Structure", "citation": "27(5):846–852.e3 · doi:10.1016/j.str.2019.01.016", "finding": "Structural work defined how MRG15 binding releases ASH1L catalytic autoinhibition and activates its H3K36 methyltransferase function.", "tags": [ "MRG15", "autoinhibition", "H3K36", "structure" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/30827841/" }, { "label": "DOI", "href": "https://doi.org/10.1016/j.str.2019.01.016" } ], "doi": "10.1016/j.str.2019.01.016", "pmid": "30827841", "primaryQuestion": "How does MRG15 binding release ASH1L autoinhibition and activate H3K36 methyltransferase activity?", "primaryQuestionRationale": "The purified-complex structure and biochemistry explain catalytic activation by MRG15 but do not establish the consequence of an individual human variant.", "sourceNumber": 35, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Purified-complex structure and biochemistry do not establish the functional consequence of an individual human variant or a clinical severity relationship.", "sourceCheckedOn": "2026-07-24" }, { "year": "2019", "authors": "Hou P, Lee JS, Zhao R, et al.", "title": "Structural insights into stimulation of Ash1L's H3K36 methyltransferase activity through Mrg15 binding", "journal": "Structure", "citation": "27(5):837–845.e3 · doi:10.1016/j.str.2019.01.015", "finding": "Defines MRG15-associated activation and the autoinhibitory architecture of the ASH1L catalytic region.", "tags": [ "MRG15", "structure", "autoinhibition", "H3K36" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/30827843/" }, { "label": "DOI", "href": "https://doi.org/10.1016/j.str.2019.01.015" } ], "doi": "10.1016/j.str.2019.01.015", "pmid": "30827843", "primaryQuestion": "What structural features explain stimulation of Ash1L H3K36 methyltransferase activity through Mrg15 binding?", "primaryQuestionRationale": "This structural analysis defines the Mrg15-associated activation architecture of the catalytic region without functioning as a clinical phenotype or variant-severity assay.", "sourceNumber": 36, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Structural complex evidence is not a clinical phenotype or variant-severity assay.", "sourceCheckedOn": "2026-07-24" }, { "year": "2018", "authors": "Castiglioni I, Caccia R, Garcia-Manteiga JM, et al.", "title": "The Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression", "journal": "Nature Communications", "citation": "9:5026 · doi:10.1038/s41467-018-07313-8", "finding": "In mouse muscle and myoblast systems, Ash1l opposed Polycomb repression at selected myogenic genes, activated Cdon, and supported myoblast fusion during formation and regeneration.", "tags": [ "skeletal muscle", "myoblast", "fusion", "Cdon", "regeneration", "mouse" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/s41467-018-07313-8" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/30487570/" } ], "doi": "10.1038/s41467-018-07313-8", "pmid": "30487570", "primaryQuestion": "How does Ash1l promote myoblast fusion and muscle regeneration through regulation of Cdon?", "primaryQuestionRationale": "The mouse muscle and myoblast findings support a direct role in fusion and regeneration but do not establish a primary human myopathy or explain every motor-related feature.", "sourceNumber": 37, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "Direct muscle-lineage evidence, but not proof of a primary human myopathy or an explanation for every tone, gait, fatigue, or recovery finding.", "sourceCheckedOn": "2026-07-24" }, { "year": "2017", "authors": "Li G, Ye Z, Shi C, et al.", "title": "The histone methyltransferase Ash1l is required for epidermal homeostasis in mice", "journal": "Scientific Reports", "citation": "7:45401 · doi:10.1038/srep45401", "finding": "Historically Yale-affiliated study showing an extra-neural role in epidermal differentiation, proliferation, and wound repair in mice.", "tags": [ "Yale affiliated", "skin", "epidermis", "wound healing", "mouse" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/srep45401" }, { "label": "DOI", "href": "https://doi.org/10.1038/srep45401" } ], "doi": "10.1038/srep45401", "pmid": "28374742", "primaryQuestion": "Is Ash1l required for epidermal differentiation, proliferation, homeostasis, and wound repair in mice?", "primaryQuestionRationale": "The mouse epidermal model demonstrates a skin-lineage requirement for Ash1l without establishing a universal skin phenotype in people with ASH1L-related neurodevelopmental disorder.", "sourceNumber": 38, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "Mouse epidermal biology does not establish a universal human skin phenotype in ASH1L-related NDD.", "sourceCheckedOn": "2026-07-24" }, { "year": "2017", "authors": "Xia M, Liu J, Liu S, et al.", "title": "ASH1L and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T-cell autoimmunity", "journal": "Nature Communications", "citation": "8:15818 · doi:10.1038/ncomms15818", "finding": "Supports an Ash1l-dependent chromatin mechanism in induced regulatory T-cell polarization and autoimmunity models.", "tags": [ "immune", "Treg", "Smad3", "chromatin" ], "links": [ { "label": "Full text", "href": "https://www.nature.com/articles/ncomms15818" }, { "label": "DOI", "href": "https://doi.org/10.1038/ncomms15818" } ], "doi": "10.1038/ncomms15818", "pmid": "28598443", "primaryQuestion": "How do ASH1L and lnc-Smad3 regulate Smad3 locus accessibility during induced regulatory T-cell polarization and autoimmunity?", "primaryQuestionRationale": "The immune-model study identifies an Ash1l-dependent chromatin mechanism in induced regulatory T cells but does not demonstrate an immune phenotype in heterozygous ASH1L-related disorder.", "sourceNumber": 39, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "Immune model evidence does not establish an immune phenotype in heterozygous ASH1L-related disorder.", "sourceCheckedOn": "2026-07-24" }, { "year": "2017", "authors": "Huang C, Yang F, Zhang Z, et al.", "title": "MRG15 stimulates ASH1L H3K36 methyltransferase activity", "journal": "Nature Communications", "citation": "8:16099 · doi:10.1038/s41467-017-01897-3", "finding": "Biochemical and structural work supporting MRG15-dependent activation of ASH1L methyltransferase activity.", "tags": [ "MRG15", "H3K36", "biochemistry", "structure" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1038/s41467-017-01897-3" } ], "doi": "10.1038/s41467-017-01897-3", "pmid": "29158494", "primaryQuestion": "Does MRG15 stimulate ASH1L H3K36 methyltransferase activity in biochemical and cellular systems?", "primaryQuestionRationale": "The biochemical and structural evidence supports MRG15-dependent catalytic activation while leaving patient-specific dysfunction untested.", "sourceNumber": 40, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Cofactor activation in purified and cellular systems does not establish patient-specific dysfunction.", "sourceCheckedOn": "2026-07-24" }, { "year": "2017", "authors": "Okamoto N, Miya F, Tsunoda T, et al.", "title": "Novel MCA/ID syndrome with ASH1L mutation", "journal": "American Journal of Medical Genetics Part A", "citation": "173(6):1644–1648 · doi:10.1002/ajmg.a.38193", "finding": "Early syndrome-level case report that helped establish the clinical association between disruptive ASH1L variation and neurodevelopmental disorder.", "tags": [ "human", "case report", "MCA", "intellectual disability" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1002/ajmg.a.38193" } ], "doi": "10.1002/ajmg.a.38193", "pmid": "28394464", "primaryQuestion": "What clinical association between an ASH1L variant and multiple congenital anomalies with intellectual disability was reported in this early case?", "primaryQuestionRationale": "The case helped establish a syndrome-level ASH1L association but cannot by itself define the disorder or estimate the frequency of any feature.", "sourceNumber": 41, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "Single early case; not a complete syndrome definition or feature-frequency estimate.", "sourceCheckedOn": "2026-07-24" }, { "year": "2016", "authors": "Zhu L, et al.", "title": "Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α", "journal": "Scientific Reports", "citation": "6:26597 · doi:10.1038/srep26597", "finding": "Shows activity-dependent recruitment of Ash1l and H3K36me2 at the Nrxn1α promoter in mouse cortical neurons.", "tags": [ "neurexin", "neuronal activity", "H3K36", "cortical neurons" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1038/srep26597" } ], "doi": "10.1038/srep26597", "pmid": "27229316", "primaryQuestion": "How does activity-dependent Ash1l recruitment affect Nrxn1α promoter chromatin and expression in mouse cortical neurons?", "primaryQuestionRationale": "The one-locus neuronal model links Ash1l and H3K36me2 to activity-dependent Nrxn1α regulation without establishing fluctuating human cognition, regression, or treatment response.", "sourceNumber": 42, "researchArea": "Neural systems", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "One-locus in-vitro/model result; it does not establish fluctuating human cognition, regression, or treatment response.", "sourceCheckedOn": "2026-07-24" }, { "year": "2015", "authors": "Jones M, Chase J, Xu J, et al.", "title": "ASH1L controls quiescence and self-renewal potential in hematopoietic stem cells", "journal": "Journal of Clinical Investigation", "citation": "125(5):2007–2020 · doi:10.1172/JCI78124", "finding": "Establishes an ASH1L role in hematopoietic stem-cell quiescence and self-renewal.", "tags": [ "hematopoietic", "stem cell", "quiescence", "extra-neural" ], "links": [ { "label": "Full text", "href": "https://www.jci.org/articles/view/78124" }, { "label": "DOI", "href": "https://doi.org/10.1172/JCI78124" } ], "doi": "10.1172/jci78124", "pmid": "25866973", "primaryQuestion": "How does ASH1L regulate quiescence and self-renewal in hematopoietic stem cells?", "primaryQuestionRationale": "The hematopoietic stem-cell mechanism provides direct blood-lineage biology but is not evidence of a blood or immune manifestation in ASH1L-related neurodevelopmental disorder.", "sourceNumber": 43, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "Mechanistic tissue context, not evidence of a blood or immune manifestation in an individual with ASH1L-related NDD.", "sourceCheckedOn": "2026-07-24" }, { "year": "2013", "authors": "Miyazaki H, Higashimoto K, Yada Y, et al.", "title": "ASH1L methylates Lys36 of histone H3 independently of transcriptional elongation to counteract Polycomb silencing", "journal": "PLOS Genetics", "citation": "9(11):e1003897 · doi:10.1371/journal.pgen.1003897", "finding": "ASH1L catalytic activity opposed Polycomb repression and supported timely activation of selected developmental genes in mouse differentiation systems.", "tags": [ "H3K36", "Polycomb", "H3K27me3", "timing", "differentiation" ], "links": [ { "label": "Full text", "href": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003897" }, { "label": "DOI", "href": "https://doi.org/10.1371/journal.pgen.1003897" } ], "doi": "10.1371/journal.pgen.1003897", "pmid": "24244179", "primaryQuestion": "How does ASH1L-mediated H3K36 methylation counteract Polycomb silencing during activation of selected developmental genes?", "primaryQuestionRationale": "The differentiation models support a selected-locus mechanism for opposing Polycomb repression but do not demonstrate genome-wide spreading or failed bivalent-domain resolution in patient cells.", "sourceNumber": 44, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Selected-locus model evidence; it does not establish genome-wide H3K27me3 spread or failed bivalent-domain resolution in human ASH1L patient cells.", "sourceCheckedOn": "2026-07-24" }, { "year": "2013", "authors": "Xia M, Liu J, Wu X, et al.", "title": "Histone methyltransferase Ash1l suppresses IL-6 production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20", "journal": "Immunity", "citation": "39(3):470–481 · doi:10.1016/j.immuni.2013.08.016", "finding": "Defines an Ash1l–A20/Tnfaip3 mechanism restraining inflammatory signaling in macrophage and mouse models.", "tags": [ "immune", "A20", "TNFAIP3", "IL-6", "macrophage" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1016/j.immuni.2013.08.016" } ], "doi": "10.1016/j.immuni.2013.08.016", "pmid": "24012418", "primaryQuestion": "How does Ash1l restrain IL-6 production and inflammatory autoimmunity through A20 in macrophage and mouse models?", "primaryQuestionRationale": "The Ash1l-A20 mechanism explains inflammatory control in macrophage and mouse systems without establishing a cytokine or immune phenotype in human ASH1L haploinsufficiency.", "sourceNumber": 45, "researchArea": "Extra-neural", "evidenceCategory": "Systems", "publicationStatus": "Peer reviewed", "interpretationLimit": "Tissue- and model-specific; it does not establish a human cytokine or immune phenotype in ASH1L haploinsufficiency.", "sourceCheckedOn": "2026-07-24" }, { "year": "2011", "authors": "Tanaka Y, Katagiri Z, Kawahashi K, et al.", "title": "Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression", "journal": "PLOS ONE", "citation": "6(11):e28171 · doi:10.1371/journal.pone.0028171", "finding": "Historically Yale-affiliated molecular work examining ASH1L-dependent Hox regulation and chromatin function.", "tags": [ "Yale affiliated", "Hox", "H3K36", "molecular" ], "links": [ { "label": "Full text", "href": "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028171" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/22140534/" } ], "doi": "10.1371/journal.pone.0028171", "pmid": "22140534", "primaryQuestion": "How does ASH1L contribute to Hox gene regulation through H3K36 methyltransferase-linked chromatin activity?", "primaryQuestionRationale": "The study supplies foundational gene-regulation evidence from a non-neurodevelopmental setting rather than direct evidence about human phenotype.", "sourceNumber": 46, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Foundational gene-regulation evidence from a non-neurodevelopmental context; not human phenotype evidence.", "sourceCheckedOn": "2026-07-24" }, { "year": "2011", "authors": "An S, Yeo KJ, Jeon YH, Song JJ", "title": "Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism", "journal": "Journal of Biological Chemistry", "citation": "286(10):8369–8374 · doi:10.1074/jbc.M110.203380", "finding": "Foundational catalytic-domain structure demonstrating an autoinhibitory loop that blocks substrate access in the inactive state.", "tags": [ "structure", "SET", "autoinhibition", "catalytic domain" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/21239497/" }, { "label": "DOI", "href": "https://doi.org/10.1074/jbc.M110.203380" } ], "doi": "10.1074/jbc.m110.203380", "pmid": "21239497", "primaryQuestion": "What structural feature of the human ASH1L catalytic domain explains its autoinhibited state?", "primaryQuestionRationale": "The catalytic-domain crystal structure identifies a substrate-blocking autoinhibitory loop but cannot assign cell-type effects or the consequences of clinical variants.", "sourceNumber": 47, "researchArea": "Molecular function", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Purified catalytic-domain structure does not define cell-type phenotype or clinical variant effect.", "sourceCheckedOn": "2026-07-24" }, { "year": "2011", "authors": "Yuan W, Xu M, Huang C, Liu N, Chen S, Zhu B", "title": "H3K36 methylation antagonizes PRC2-mediated H3K27 methylation", "journal": "Journal of Biological Chemistry", "citation": "286(10):7983–7989 · doi:10.1074/jbc.M110.194027", "finding": "Biochemical evidence that H3K36 methylation can directly inhibit PRC2-mediated H3K27 methylation.", "tags": [ "H3K36", "H3K27me3", "PRC2", "biochemistry" ], "links": [ { "label": "Full text", "href": "https://pmc.ncbi.nlm.nih.gov/articles/PMC3048685/" }, { "label": "DOI", "href": "https://doi.org/10.1074/jbc.M110.194027" } ], "doi": "10.1074/jbc.m110.194027", "pmid": "21239496", "primaryQuestion": "Does H3K36 methylation directly antagonize PRC2-mediated H3K27 methylation?", "primaryQuestionRationale": "This mark-level biochemical result provides general chromatin context but does not show that ASH1L haploinsufficiency causes global Polycomb spreading or a uniform clinical state.", "sourceNumber": 48, "researchArea": "Methods or context", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Mark-level antagonism does not show that ASH1L haploinsufficiency produces global Polycomb spreading or a uniform human clinical state.", "sourceCheckedOn": "2026-07-24" }, { "year": "2006", "authors": "Bernstein BE, Mikkelsen TS, Xie X, et al.", "title": "A bivalent chromatin structure marks key developmental genes in embryonic stem cells", "journal": "Cell", "citation": "125(2):315–326 · doi:10.1016/j.cell.2006.02.041", "finding": "Foundational evidence for H3K4me3/H3K27me3 bivalent domains that poise developmental regulators in embryonic stem cells.", "tags": [ "bivalency", "H3K4me3", "H3K27me3", "stem cells", "development" ], "links": [ { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/16630819/" }, { "label": "DOI", "href": "https://doi.org/10.1016/j.cell.2006.02.041" } ], "doi": "10.1016/j.cell.2006.02.041", "pmid": "16630819", "primaryQuestion": "How do bivalent H3K4me3 and H3K27me3 domains mark developmental genes in embryonic stem cells?", "primaryQuestionRationale": "The study establishes bivalency as a general developmental-chromatin concept without demonstrating abnormal bivalent-domain resolution in ASH1L patient cells.", "sourceNumber": 49, "researchArea": "Methods or context", "evidenceCategory": "Molecular", "publicationStatus": "Peer reviewed", "interpretationLimit": "Bivalency is a general developmental-chromatin concept. Its abnormal resolution has not yet been demonstrated broadly in ASH1L patient cells.", "sourceCheckedOn": "2026-07-24" }, { "year": "2026", "authors": "Taşdelen E, Tekbaş UC, Kolkıran A, Çetinkaya S, Kılıç M, Sezer A", "title": "Atypical Biallelic Inheritance in \"Dominant\" Genes: Evidence From a Large-Scale Consanguineus Exome Cohort", "journal": "American Journal of Medical Genetics Part A", "citation": "200(9):2088–2098 · doi:10.1002/ajmg.a.70231", "finding": "A retrospective consanguineous exome cohort included an ASH1L observation among selected biallelic findings in genes usually associated with dominant disease. The authors interpreted the ASH1L context as potentially hypomorphic and dosage-sensitive.", "tags": [ "human genetics", "biallelic", "consanguinity", "dosage", "hypomorphic", "inheritance" ], "links": [ { "label": "DOI", "href": "https://doi.org/10.1002/ajmg.a.70231" }, { "label": "PubMed", "href": "https://pubmed.ncbi.nlm.nih.gov/42316479/" } ], "doi": "10.1002/ajmg.a.70231", "pmid": "42316479", "primaryQuestion": "Can selected biallelic ASH1L variants produce an allelic or dosage context distinct from established heterozygous haploinsufficiency?", "primaryQuestionRationale": "The human cohort places one ASH1L observation within a broader study of atypical biallelic findings, supporting allele-specific follow-up without establishing a general recessive ASH1L disorder.", "sourceNumber": 50, "researchArea": "Human disorder", "evidenceCategory": "Human", "publicationStatus": "Peer reviewed", "interpretationLimit": "This selected cohort observation does not establish a broadly recessive ASH1L disorder, a biallelic severity rule, or a contradiction of the established autosomal-dominant haploinsufficiency relationship. The exact alleles and measured functional dosage still determine what can be concluded.", "sourceCheckedOn": "2026-08-14" } ] }