MYT1L

protein-coding

myelin transcription factor 1 like, the group of Zinc fingers C2H2C-type

Gene summary

This gene encodes a member of the zinc finger superfamily of transcription factors whose expression, thus far, has been found only in neuronal tissues. The encoded protein belongs to a novel class of cystein-cystein-histidine-cystein zinc finger proteins that function in the developing mammalian central nervous system. Forced expression of this gene in combination with the basic helix-loop-helix transcription factor NeuroD1 and the transcription factors POU class 3 homeobox 2 and achaete-scute family basic helix-loop-helix transcription factor 1 can convert fetal and postnatal human fibroblasts into induced neuronal cells, which are able to generate action potentials. Mutations in this gene have been associated with an autosomal dominant form of cognitive disability and with autism spectrum disorder. Alternative splicing results in multiple variants. [provided by RefSeq, Jul 2017]

MANE transcript

NM_001303052.2

Inheritance

ClinVar variants

P:123U:251B:127

Top phenotype

Intellectual developmental disorder, autosomal dominant 39

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr2:1,789,113-2,331,664

External References & Databases

Ensembl (ENSG00000186487)

Transcript & Mutation Effects

hg38 • Region Span ~542.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability, autosomal dominant 39STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014678

Submitter: Ambry Genetics

intellectual disability, autosomal dominant 39DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014678

Submitter: G2P

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*MYT1L* encodes a neuron-specific transcription factor. *MYT1L* was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2007 (de Ligt et al., PMID: 23033978). The disorder is characterized by developmental delay with significant speech and language delay, mild to severe intellectual disability, behavioral disorders including autism, hyperphagia, obesity or overweight, and dysmorphic features. Other variable features include hypotonia, seizures, and brain MRI abnormalities. Individuals with 2p25.3 deletions encompassing *MYT1L* exhibit an overlapping phenotype, indicating that *MYT1L* is the causal gene (PMID: 2523284). At least ten unique *MYT1L* sequence variants have been reported. Ten variants (nonsense, frameshift, splice site, and missense) that have been reported in ten probands in four publications (PMIDs: 23033978, 25232846, 28859103, 30055078) are included in this curation. All variants occurred *de novo*. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by animal models and *in vitro* functional studies. Myt1l plays a key role in neuronal differentiation by repressing expression of non-neuronal genes during neuron differentiation (PMID: 28379941) and promotes differentiation of oligodendrocyte precursor cells (PMID: 29397565). In summary, there is definitive evidence supporting the relationship between *MYT1L* and autosomal dominant syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 18, 2020 (SOP Version 7). As of October 2025, this record underwent administrative updates to update scoring to be consistent with SOP Version 11. No new evidence has been added.

intellectual disability, autosomal dominant 39STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014678

Submitter: PanelApp Australia

intellectual disability, autosomal dominant 39STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014678

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability, autosomal dominant 39STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014678

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 39AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21990140; 23033978; 23160955; 25232846; 26240977; 30055078

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYT1L variants in ClinVar

17 Conditions Cataloged

not providedTotal: 362

Intellectual disability, autosomal dominant 39Total: 123

Inborn genetic diseasesTotal: 99

MYT1L-related disorderTotal: 62

not specifiedTotal: 59

Intellectual disabilityTotal: 13

Early onset severe obesityTotal: 10

See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001303052.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		3 clinvar	84 clinvar	8 clinvar	96
missense	4 clinvar	32 clinvar	240 clinvar	32 clinvar	3 clinvar	311
nonsense	24 clinvar	11 clinvar	1 clinvar			36
start loss			1 clinvar			1
frameshift	26 clinvar	16 clinvar	5 clinvar			47
splice donor/acceptor (+/-2bp)	4 clinvar	5 clinvar	1 clinvar			10
Total	59	64	251	116	11	501

Highest pathogenic variant AF is 0.000006569094

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 93 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001303052.2	RefSeq	NP_001289981.1	20	MANE Select
ENST00000647738.2	Ensembl	ENSP00000497479.2	20	MANE Select
NM_001329844.2	RefSeq	NP_001316773.1	20	Standard
NM_001329845.1	RefSeq	NP_001316774.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription by RNA polymerase II
nervous system development
neuron differentiation
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
zinc ion binding

Cellular Component

nucleus
chromosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000428368
Coding exons: 20
Length: 542148
Individuals with no LoFs: 124643
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 124645
p: 0.00000802

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.77	365	727	0.502	0.0000456	7928
Missense (PolyPhen)		91	308	0.29545		3271
Synonymous	2.25	254	304	0.836	0.0000229	2078
Loss of Function	6.71	1	54.4	0.0184	0.00000270	674

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000089	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that plays a key role in neuronal differentiation by specifically repressing expression of non- neuronal genes during neuron differentiation. In contrast to other transcription repressors that inhibit specific lineages, mediates repression of multiple differentiation programs. Also represses expression of negative regulators of neurogenesis, such as members of the Notch signaling pathway, including HES1. The combination of three transcription factors, ASCL1, POU3F2/BRN2 and MYT1L, is sufficient to reprogram fibroblasts and other somatic cells into induced neuronal (iN) cells in vitro. Directly binds the 5'-AAGTT- 3' core motif present on the promoter of target genes and represses transcription by recruiting a multiprotein complex containing SIN3B. The 5'-AAGTT-3' core motif is absent from the promoter of neural genes. {ECO:0000250|UniProtKB:P97500}.;
Disease: DISEASE: Mental retardation, autosomal dominant 39 (MRD39) [MIM:616521]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD39 patients show delayed psychomotor development and autistic features. {ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23160955}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.116

Intolerance Scores

RVIS EVS: -1.51
RVIS percentile EVS: 3.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.336

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium