Submission Details

The EHMT1 gene has been associated with autosomal dominant Kleefstra syndrome (AD KS) using the ClinGen Clinical Validity Framework as of 5/30/2018. This association was made using case-level data, and experimental data. At least 14 unique variants (e.g. missense, nonsense, frameshift, large deletion) have been reported in humans (Williemsen 2012). Though this evaluation focuses on sequence-level variation in the EHMT1 gene, Kleefstra syndrome is also caused by larger deletions of the 9q34 region; these deletions range in size and have variable breakpoints, but all include at least part of the EHMT1 gene. Please see GeneReviews for further discussion of the molecular mechanism of this disorder. EHMT1 was first associated with this disease in humans as early as 2005 (Kleefstra et al.). Association is seen in at least 14 probands in more than 2 publications (22670141, 27651234). Variants in this gene were found to be de novo in at least 6 cases. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by mice models, drosophila models, cell culture models, expression studies, and functional alteration studies implicating variants in this gene with neuronal dysfunction. In summary, EHMT1 is definitively associated with AD KS. 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 ClinGen ID/Autism Working Group on 6/6/2018.

EHMT1 was first reported in relation to autosomal dominant Kleefstra syndrome in 2005 (Kleefstra et al., PMID: 15805155). Kleefstra syndrome is characterized by developmental delay, limited or absent speech, intellectual disability, autism or autistic-like features, hypotonia, and distinctive facial features. Additional findings may include heart abnormalities, kidney defects, and epilepsy. Though this evaluation focuses on sequence-level variation in the EHMT1 gene, Kleefstra syndrome is also caused by larger deletions of the 9q34 region; these deletions vary in size and have variable breakpoints, but all include at least part of the EHMT1 gene.

Ten variants (frameshift, nonsense, splice, missense) that have been reported in 10 probands in three publications (PMIDs: 22670141, 27651234, 28361100) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease association is also supported by mouse models, drosophila models, cell culture models, and functional alteration studies implicating variants in this gene in neuronal dysfunction.

In summary, there is definitive evidence supporting the relationship between EHMT1 and autosomal dominant Kleefstra syndrome. 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 ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 6, 2018 (SOP Version 5).