Intellectual disability
Gene: DOT1L

DOT1L (DOT1 like histone lysine methyltransferase)
EnsemblGeneIds (GRCh38): ENSG00000104885
EnsemblGeneIds (GRCh37): ENSG00000104885
OMIM: 607375, Gene2Phenotype
DOT1L is in 3 panels

1 review

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are more than 20 individuals reported in literature with heterozygous de novo variants in DOT1L, and a neurodevelopmental disorder with variable congenital anomalies. The NDD manifested in speech and motor developmental delay, ASD, and intellectual disability (reported as severe in at least 5 probands). Hence, this gene should be rated Green on Intellectual disability.
Created: 23 Oct 2026, 2:04 p.m. | Last Modified: 23 Oct 2026, 2:05 p.m.

Panel Version: 11.53

PMID: 40494548 Maroni et al., 2026
Report of a cohort of 16 individuals (12 females, 4 males) with neurodevelopmental disorders and monoallelic DOT1L variants, including a frameshift deletion, an in-frame deletion, a nonsense, and missense variants clustered in the catalytic domain. Inheritance of variants was de novo (10/16), maternal (1/16, the mother had distinctive craniofacial features and skeletal phenotype), or unknown (5/16).
Phenotypic spectrum: craniofacial anomalies (14/16), intellectual disability (4/16), language delay (13/16), motor delay (9/16), a diagnosis of ASD (4/16) and seizures/epilepsy (3/16).

Functional evidence: In primary cortical neurons, Dot1l knockdown disrupts transcription of synaptic genes, neuron branching, expression of a synaptic protein and neuronal activity. Zebrafish and mouse models, showed developmental deficits and sex-specific social behavioural changes (exaggerated responses to sensory stimuli, change in vocalisations, motor development, social preference).

PMID: 37827158 Nil et al., 2023
Study identified nine unrelated individuals with seven different heterozygous missense variants in DOT1L. Variants confirmed to be de novo in 8 probands. All individuals had some degree of global developmental delay/intellectual disability (severe in 5, mild in 1 individual, and 3 of unspecified severity), and most had one or more major congenital anomalies. These were variable and included urogenital anomalies (5/9), cardiac anomalies (5/9: ASD, VSD, cardiomyopathy), brain anomalies (6/9), muscoskeletal anomalies (5/9: hip laxity x3, low exercise endurance x1, anomalous ribs & vertebrae x1), hypotonia (5/9), microcephaly (4/9, though <1.0% only for 1 proband).

DOT1L is associated with AD Nil-Deshwar neurodevelopmental syndrome, OMIM:621265 (OMIM accessed 23rd Oct 2026).
Sources: Literature
Created: 23 Oct 2026, 2:02 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Nil-Deshwar neurodevelopmental syndrome, OMIM:621265; Nil-Deshwar neurodevelopmental syndrome, MONDO:0979246

Publications

Created: 23 Oct 2026, 2:02 p.m.
Last Modified: 23 Oct 2026, 2:05 p.m.
Panel version: 11.52

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Amber
Literature

Phenotypes

Nil-Deshwar neurodevelopmental syndrome, OMIM:621265
Nil-Deshwar neurodevelopmental syndrome, MONDO:0979246

Tags

Q4_26_promote_green

OMIM

607375

Clinvar variants

Variants in DOT1L

Penetrance

None

Publications

Panels with this gene

History Filter Activity

23 Oct 2026, Gel status: 2

Entity classified by Genomics England curator

Ida Ertmanska (Genomics England Curator)

Gene: dot1l has been classified as Amber List (Moderate Evidence).

23 Oct 2026, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes

Ida Ertmanska (Genomics England Curator)

gene: DOT1L was added gene: DOT1L was added to Intellectual disability. Sources: Literature Q4_26_promote_green tags were added to gene: DOT1L. Mode of inheritance for gene: DOT1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DOT1L were set to 37827158; 40494548 Phenotypes for gene: DOT1L were set to Nil-Deshwar neurodevelopmental syndrome, OMIM:621265; Nil-Deshwar neurodevelopmental syndrome, MONDO:0979246 Review for gene: DOT1L was set to GREEN

Intellectual disability Gene: DOT1L