Intellectual disability
Gene: KMT2E

KMT2E (lysine methyltransferase 2E)
EnsemblGeneIds (GRCh38): ENSG00000005483
EnsemblGeneIds (GRCh37): ENSG00000005483
OMIM: 608444, Gene2Phenotype
KMT2E is in 4 panels

4 reviews

Arina Puzriakova (Genomics England Curator)

Comment on publications: PMID: 34321323 - 18 additional patients from 17 families with genetically confirmed ODLURO
Created: 1 Sep 2021, 4:18 p.m. | Last Modified: 1 Sep 2021, 4:18 p.m.

Panel Version: 3.1250

Created: 1 Sep 2021, 4:18 p.m.
Last Modified: 1 Sep 2021, 4:18 p.m.
Panel version: 3.1250

Louise Daugherty (Genomics England Curator)

Comment on phenotypes: added OMIM MIM id
Created: 19 Aug 2019, 9:54 a.m. | Last Modified: 19 Aug 2019, 9:54 a.m.

Panel Version: 2.1014

Created: 19 Aug 2019, 9:54 a.m.
Last Modified: 19 Aug 2019, 9:54 a.m.
Panel version: 2.1014

Eleanor Williams (Genomics England Curator)

Comment on list classification: Sufficient cases with ID to rate green.
Created: 13 Jun 2019, 11:05 a.m.

Not associated with any phenotype in OMIM. Confirmed association with Intellectual disability in Gene2Phenotype (monoallelic)

PMID: 31079897 O'Donnell-Luria et al 2019 - report on additional 35 individuals with heterozygous variants in KMT2E and 3 previously reported males. New cases were ascertained from GeneMatcher through the Matchmaker Exchange Network and MyGene2. 34 individuals from 32 families were found to have single-nucleotide or indel variants in KMT2E, and four additional individuals had copy-number variants encompassing KMT2E. 21 unrelated individuals reported with mild to severe intellectual disability (2 severe, 5 moderate).

Sufficient cases with likely disease-causing variants to rate as green.
Created: 13 Jun 2019, 11:02 a.m.

Created: 13 Jun 2019, 11:02 a.m.

Panel version: 2.864

Konstantinos Varvagiannis (Other)

Green List (high evidence)

In a collaborative study, O'Donnell-Luria et al. (2019 - https://doi.org/10.1101/566091 - DDD study among the co-authors) report on 38 individuals from 36 families with heterozygous KMT2E variants. Some of these individuals were previously included in previous publications.

Developmental delay, intellectual disability, epilepsy and ASD were among the features reported, albeit of variable degree and not universal.

34 of 38 individuals had SNVs or indel variants in KMT2E and 4 individuals had CNVs spanning KMT2E (in one case intragenic, in 3 further as a contiguous gene deletion).

For 26 (of 38 individuals) the variant had arisen as a de novo event while in some cases parental sample(s) was/were unavailable to confirm the de novo occurrence or origin (from a reportedly affected parent). The variant in one family was inherited from a parent for whom information on affected/unaffected status was unavailable.

As for the variants reported: 30 were protein-truncating (of which 23 predicted to produce transcripts subject to NMD). 4 were missense. 4 were CNVs (de novo deletions, of which 1 intragenic).

Truncating variants and deletions of KMT2E suggest haploinsufficiency as the underlying mechanism for this category of variants (KMT2E has a pLI of 1 in gnomAD).

However, the somewhat different phenotype related to missense variants (degree of ID, epilepsy in all, microcephaly in some versus macrocephaly in subjects with truncating variants) may suggest a different mechanism for these variants eg. gain of function or dominant negative effect. There was no clustering observed for the missense variants reported.

Expressivity of certain features may be variable between males and females.

As the authors note : KMT2E encodes a member of the lysine N-methyltransferase 2 family, a family of enzymes with critical role in H3K4 methylation. It is highly expressed in brain, particularly during fetal development. Several monogenic neurodevelopmental disorders due to impaired regulation of H3K4 methylation are known (eg. due to KMT2D/C/B/A mutations, etc). Studies suggest that KMT2E may lack intrinsic methyltransferase activity although it may have an indirect effect on H3K4 methylation. In contrast to other members of the KMT2 family functioning as global activators of open chromatin, KMT2E is believed to be a repressor (although it's function in gene transcription regulation needs to be clarified).

A neurological phenotype of Kmt2e (Mll5) deficiency mouse models has not been reported (features included growth restriction, impaired hematopoiesis, etc).

KMT2E is not associated with any phenotype in OMIM. The gene is included in the DD panel of G2P, associated with Intellectual disability (disease confidence: confirmed / mutation consequence registered in the db : LoF).
KMT2E is included in gene panels for ID offered by some diagnostic laboratories (eg. among those participating in the study).

As a result, this gene can be considered for upgrade to green (or amber).
Created: 17 Mar 2019, 10:12 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size

Publications

https://doi.org/10.1101/56609

Variants in this GENE are reported as part of current diagnostic practice

Created: 17 Mar 2019, 10:12 a.m.

Panel version: 2.784

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Green
Victorian Clinical Genetics Services

Phenotypes

O'Donnell-Luria-Rodan syndrome, 618512
Global developmental delay
Intellectual disability
Autism
Seizures
Abnormality of skull size

OMIM

608444

Clinvar variants

Variants in KMT2E

Penetrance

None

Publications

Panels with this gene

History Filter Activity

1 Sep 2021, Gel status: 3

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: KMT2E were set to 31079897

19 Aug 2019, Gel status: 3

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: KMT2E were changed from Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size to O'Donnell-Luria-Rodan syndrome, 618512; Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size

13 Jun 2019, Gel status: 3