Kleefstra Syndrome via the EHMT1 Gene

Kleefstra syndrome (KS; OMIM:610253), formerly 9q subetelomeric deletion syndrome (9qSTD), is a cognitive disorder characterized by moderate to severe intellectual disability, childhood hypotonia and distinct facial features. Craniofacial features commonly seen in KS patients include: a flat face with hypertelorism, upslanting palpebral fissures, brachycephaly, tented upper lip with an everted lower lip and prognathism (Kleefstra et al. Am J Hu Genet 79(2):370-377, 2006). Aggression and behavioral problems in KS patients often have adolescent or adult onset. Variable features of KS that are seen in a subset of patients include seizures, hearing loss, cardiac anomaly, male genital defects, obesity and synophrys (Willemsen et al. Mol Syndromol 2(3-5):202-212, 2011).

Kleefstra syndrome is caused by dominant loss-of-function mutations in or deletions of the EHMT1 gene. Nearly all cases of KS are sporadic, resulting from de novo mutations. KS phenotypes are similar in patients with point mutations in the EHMT1 gene and those with subtelomeric deletions of chromosome 9 (Kleefstra et al., 2006). The severity of the disease generally prevents inheritance of KS. A rare case of autosomal dominant inheritance of KS was reported where the parent was found to be mosaic for an EHMT1 mutation (Rump et al. Eu J Hu Genet 21(8):887-890, 2013). Mutations in EHMT1 are found in ~25% of KS cases (Kleefstra et al. Am J Hu Genet 91(1):73-82, 2012). Patients with gross duplications of 9q34.3 that include the EHMT1 gene have been reported to have learning disabilities and speech problems, suggesting that EHMT1 overexpression is also detrimental to cognitive development (Yatsenko et al. Hum Genet 131(12):1895-1910, 2012).

EHMT1 encodes the histone methyltransferase EHMT1. Histones contain amino acid ‘tails’ which can be modified in a variety of ways. Histone tail modifications regulate chromatin structure and influence which regions of the genome are transcribed. EHMT1 is a putative histone 3 lysine 9 (H3K9) methyltransferase. Methylation of histone 3 lysine 9 leads to transcriptional repression. It is hypothesized that misexpression of EHMT1 target genes, due to loss of histone methylation, underlies the KS phenotype in patients with EHMT1 mutations (Kleefstra et al., 2012).

In one study, EHMT1 mutations were found in 25% of patients who displayed core features of Kleefstra syndrome (Kleefstra et al. Am J Hu Genet 91(1):73-82, 2012).

Approximately 50% of EHMT1 variants reported in KS cases are large deletions (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the EHMT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.