Gene Validity Classification Summary

Gene/Disease Pair:

EHMT1 : Kleefstra syndrome

HGNC:24650 | MONDO_0012455
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Autism and Intellectual Disability EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Willemsen MH et al. 2012 Apr (PMID:22670141); Bock I et al. 2016 Dec 31 (PMID:27651234); Blackburn PR et al. 2017 Mar (PMID:28361100);
Proband with predicted or proven null variant 1.5 0-2 10 7 7
Willemsen MH et al. 2012 Apr (PMID:22670141);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Willemsen MH et al. 2012 Apr (PMID:22670141); Helsmoortel C et al. 2015 Aug (PMID:25081361);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Balemans MC et al. 2013 Mar 1 (PMID:23175442);
Functional Alteration Patient cells 1 0 - 2 2
Blackburn PR et al. 2017 Mar (PMID:28361100); Nagy J et al. 2017 Jul 25 (PMID:28742076);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 6 4
Iacono G et al. 2018 Mar 15. (PMID:29554304); Balemans MC et al. 2013 Mar 1 (PMID:23175442); Balemans MC et al. 2014 Feb 15 (PMID:24362066);
Cell culture model 1 0 - 2 1
Martens MB et al. 2016 Oct 21 (PMID:27767173);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
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.