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| Intellectual disability v11.53 | DOT1L | Ida Ertmanska changed review comment from: Comment on list classification: There are more than 20 individuals reported in literature with heterozygous de novo variants in DOT1L, and a neurodevelopmental disorder. The disorder 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.; to: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.53 | DOT1L | Ida Ertmanska Classified gene: DOT1L as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.53 | DOT1L | Ida Ertmanska Added comment: Comment on list classification: There are more than 20 individuals reported in literature with heterozygous de novo variants in DOT1L, and a neurodevelopmental disorder. The disorder 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.53 | DOT1L | Ida Ertmanska Gene: dot1l has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.52 | DOT1L |
Ida Ertmanska 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 Added comment: 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 |
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