EHMT1

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: KLEEFSTRA SYNDROME 1; KLEFS1

Evidence for haploinsufficiency phenotype

PubMed ID	Description
16826528	Kleefstra et al. (2006): Describes mutations in EHMT1 in individuals with features characteristic of the 9q telomere microdeletion syndrome (Kleefstra syndrome), including one de novo nonsense mutation and one de novo frameshift predicted to result in protein truncation.
19264732	Kleefstra et al. (2009): Additional changes in EHMT1 are described in individuals exhibiting features of the 9q telomere microdeletion syndrome, including a deletion only involving EHMT1, two additional nonsense mutations, and an additional frameshift mutation predicted to result in protein truncation.

Haploinsufficiency phenotype comments:

Haploinsufficiency of EHMT1 due to 9q34 microdeletions or mutations is associated with Kleefstra syndrome (KS). The core clinical KS phenotype includes moderate to severe developmental delay/intellectual disability (DD/ID), (childhood) hypotonia, and distinct facial features. Additional clinical features seen in KS may include congenital heart defects, urogenital defects, epilepsy, behavioral and psychiatric disorders, and overweight. Breakpoints of 9q34.3 deletions are variable and genotype-phenotype correlation studies have been challenged by the use of different molecular characterization methodologies, allelic heterogeneity, and the relative low prevalence of KS. See Willemsen et al., 2012 (PMID 22670141) for a recent review of the literature and discussion of genotype-phenotype correlation in KS.

• Triplosensitivity score: 1
• Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Evidence for gain of function phenotype

PubMed ID	Description
22083728	Kirov et al. (2007): A de novo duplication involving only EHMT1 was reported in a study of individuals with schizophrenia. Little other clinical information was available, though the patient was noted to be developmentally normal and to be overweight.