Submission Details

KMT2B was first reported in relation to Dystonia 28, childhood-onset and autosomal dominant intellectual developmental disorder in 2018 (Faundes et al., PMID: 29276005). Probands with dystonia have variable presentations and do not all present with intellectual disability. Additionally, some probands with intellectual disability and no dystonia phenotype share their variant with family members who present with dystonia but mild or no intellectual disability.Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. However, the phenotypic differences were determined to be a spectrum of disease rather than two distinct entities. Therefore, the following disease entities, Dystonia 28, childhood-onset and intellectual developmental disorder, autosomal dominant 68, have been lumped into one disease entity, complex neurodevelopmental disorder with motor features. Ten variants (missense, nonsense, and frameshift) that have been reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.The mechanism of pathogenicity is reported to be LOF. This gene-disease relationship is also supported by a non-human animal model (PMID: 23426673). Mice lacking KMT2B gene in adult forebrain excitatory neurons display impaired hippocampus-dependent memory function.

In summary, there is definitive evidence to support the relationship between KMT2B and autosomal dominant complex neurodevelopmental disorder with motor features. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on April 17, 2023 (SOP 9).