Congenital Heart Defect

Gene: KMT2B

Red List (low evidence)

Agree, no evidence of association with syndromic or non-syndromic CHD.

Created: 22 Nov 2023, 2:35 a.m. | Last Modified: 22 Nov 2023, 2:35 a.m.

Panel Version: 0.315

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dystonia 28,Childhood-onset; DYT28(617284); Intellectual Developmental disorder, Autosomal dominant; MRD68(619934)

Publications

• 33150406

I don't know

There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities were noted in the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) lists the KMT2B-associated complex early-onset dystonia in the Developmental Delay panel whose scope is" severe undiagnosed neurodevelopmental disorder and/or congenital anomalies, abnormal growth parameters, dysmorphic features and unusual behavioural phenotypes" and as such is part of the DD2P panel in Panel App England. Also, the KMT2B is absent from the Cardiac G2P, a publicly available resource designed for filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort of 133 patients with KMT2B variants (PMID:33150406) delineates their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.
However, the following evidence may be considered when upgrading the KMT2B gene to Green:
KMT2B methyltransferase is a family of histone-modifying enzymes (KMTs) that catalyse the methylation of lysine 4 of the Histone 3 protein and regulate transcriptional activity at the chromatin level. As methylation is critical in transcriptional changes occurring during development, it is not unexpected that deregulated methylation marks are found in developmental disorders, human aging, and cancer. A range of neurodevelopmental disorders is caused by pathogenic variants in genes regulating chromatin function and structure that display abnormal DNA methylation patterns (episignatures) in peripheral blood. Similarly, deregulation of histone lysine methylation, essential during cardiac development, is associated with cardiac disease. ( 35506254)
A recent review states that the known KMT2B paralogs (Gene Cards), KMT2A, KMT2C and KMT2D exhibit regulatory roles during heart development or disease (as defined by supporting data from multiple model systems and /or by disease association. (37504561).
One such example is the KMT2D gene that confusingly shares the same alternate name as KMT2B- MLL2 despite the different genomic locations of both genes and other differences. Molecular rearrangements of KMT2D are associated with Kabuki Syndrome 1(KS) (OMIM: 147920) where, in addition to neurodevelopmental presentation, congenital heart defect, ventricular and atrial septal defect are also part of the phenotypic spectrum.
Comparison of the methylation patterns in peripheral blood from patients with KMT2-dystonia, KMT2-Kabuki Syndrome and controls showed that most DNA regions with altered methylation patterns differ between these two disorders and controls with KMT2B being hypermethylated. The KMT2B is unique among ’chromatin neurodevelopmental disorders’ genes as its most prominent clinical feature is childhood-onset dystonia rather than developmental delay or congenital anomalies. (PMID:35506254).
The KMT2B paralogs, KMT2A and KMT2D supported by patient phenotypic presentation and likely valid functional evidence in animal models have been investigated thus far as candidate genes in genomic sequencing studies of cardiac disease, including those for patients with congenital heart defect (PMID3378394;25972376;28884922). Thus far, the function of KMT2B in the context of congenital heart disease is yet to be phenotypically confirmed and recapitulated through further research.

Created: 21 Nov 2023, 7:35 a.m. | Last Modified: 22 Nov 2023, 7:40 a.m.

Panel Version: 0.367

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

Phenotypes
Dystonia 28,Childhood-onset; DYT28(617284); Intellectual Developmental disorder, Autosomal dominant; MRD68(619934)

Publications

• PMID:29276005
• 23426673
• 33150406
• 23665959
• 37504561
• 28902362
• 21646717