Kleefstra syndrome is a rare disorder characterized by moderate to severe intellectual disability, childhood hypotonia, developmental delay and extremely limited speech capabilities. Patients often suffer from distinctive facial dysmorphia, such as brachycephaly, microcephaly, flat face, mid face hypoplasia, hypertelorism, synophrys, a full everted lower lip, a protruding tongue and prognathism. Some patients may also exhibit behavioral problems such as obsessive-compulsive disorder, stereotypic movements and aggressive behavior. Other symptoms may include sleep issues, obesity, brachydactyly and cardiovascular anomalies such as conotruncal heart defects.   

Kleefstra syndrome is a rare condition with about 200 affected individuals reported worldwide. Due to its recent discovery and the limited number of cases, the prognosis of the disorder is not completely known. The condition affects men and women equally and does not appear to have a racial or ethnic bias. 

The diagnosis can be confirmed by molecular testing of the EHMT1 gene. While there is currently no cure for the disorder, affected individuals benefit from early intervention strategies, including physical and occupational therapy, speech therapy and behavioral therapy. Patients may require medication for sleep issues, behavioral problems and to treat epilepsy.   

Kleefstra syndrome follows an autosomal dominant pattern of inheritance and is caused by large heterozygous deletions in the 9q34.3 chromosome region that result in the loss of the EHMT1 gene. This gene encodes a lysine methyltransferase responsible for the methylation of the Lys-9 residue of histone H3. The enzyme is part of the E2F6 complex that negatively regulates gene transcription. In about 25% of Kleefstra cases, patients do not have large deletions but instead have heterozygous point mutations in the EHMT1 gene that result in a non-functioning EHMT1 protein.

Recent studies have identified certain Kleefstra cases with no EHMT1 mutations but with variants in the MBD5, MLL3, SMARCB1 and NR1I3 genes respectively. As these genes all encode epigenetic regulators, their role in Kleefstra syndrome has been speculated. However, a direct causal link between the condition and these gene mutations has not yet been established.