Early onset or syndromic epilepsy

Gene: KMT2E

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:25 a.m. | Last Modified: 9 Sep 2019, 10:25 a.m.

Panel Version: 1.315

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Green List (high evidence)

AD ODLURDO. O'Donnell-Luria et al, 2019 (31079897) - 30 individuals most of whom in the first decade of life with a similar neurodev disorder. , but othOne patient had neonatal ischemic encephalopathy assoc with seizures, but otherwise only 4 ptients had epielspy most of which was controlled - most mutations resulted in truncated protein consistent with haploinsufficiency. 4 additional patients with het missense variants, which were assoc with a more severe phenotype - all had epilepsy, 3 of which had infantile epileptic encephalopathy. Vast majority of variants de novo, although family with 3 aff sibs where variant inherited from aff father.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

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

Comment on phenotypes: added OMIM MIM id

Created: 19 Aug 2019, 9:53 a.m. | Last Modified: 19 Aug 2019, 9:53 a.m.

Panel Version: 1.254

Comment on list classification: Sufficient cases to rate green.

Created: 13 Jun 2019, 10:45 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. 11 unrelated individuals had epilepsy - 3 had microdeletions, 4 missense variants, 2 frameshift, 1 nonsense and 1 a variant affecting a splice site.

Sufficient cases with likely disease-causing variants to rate as green.

Created: 13 Jun 2019, 10:44 a.m.

Comment on publications: URL was to the paper in Bioxriv. Paper is now in Am J Hum Genet

Created: 13 Jun 2019, 10:12 a.m.

Green List (high evidence)

Gene added in the ID panel (comments below). Epilepsy was a feature in - at least - 11 individuals (with all categories of variants : 4 with truncating, 3 with CNVs, 4 with missense SNVs). As a result this gene can be considered for inclusion in the current panel as green (or amber).

From the ID panel :

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).
Sources: Literature

Created: 17 Mar 2019, 10:20 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/10.1101/566091