Loss-of-Function Mutations in Euchromatin Histone Methyl Transferase 1 (EHMT1) Cause the 9q34 Subtelomeric Deletion Syndrome

Abstract

A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q-) syndrome has been estimated to be <1 Mb and comprises the euchromatin histone methyl transferase 1 gene (EHMT1). Previous studies suggested that haploinsufficiency for EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations--a nonsense mutation and a frameshift mutation--in the EHMT1 gene in patients with a typical 9q- phenotype. These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome.

A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring

“…Additional clinical findings include heart defects, renal/ urological defects, genital defects in males, autistic-like behavior in childhood, and extreme apathy or catatonic-like features after puberty. 2 The genetic causes of Kleefstra syndrome are heterozygous microdeletions in 9q34.3 and EHMT1 (euchromatic histone-lysine N-methyltransferase 1) point mutations, both leading to loss of function of the affected EHMT1 allele. 1,3 Parent-to-child transmission of Kleefstra syndrome appears to be very rare and was described only for three cases with 9q34.3 deletion 4,5 and one case with a balanced translocation.…”

Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome

“…[4][5][6][7][8] Several clinically distinct microdeletion and microduplication syndromes have been reported on the basis of data derived from these techniques, such as the 17q21.31 microdeletion syndrome 5 and the 1q41-1q42 microdeletion syndrome, 9 as well as microduplication syndromes involving 7q11.23 10,11 and 17p11.2. 12 The phenotypic characteristics of microdeletion syndromes can be caused by haploinsufficiency of single genes, for example, TCF4 (MIM 602272) in Pitt-Hopkins syndrome, 13 EHMT1 (MIM 607001) in the 9q34.3 subtelomeric deletion syndrome 14 and either CREBBP (MIM 600140) or EP300 (MIM 602700) in Rubinstein-Taybi syndrome. 15,16 The application of genome-wide array technologies with an increasing density of probes has led to the identification and localization of several genes associated with developmental disorders or abnormal brain development, 8 including CHD7 (MIM 608892) in CHARGE syndrome 17 and FOXG1(MIM 164874) in congenital Rett syndrome.…”

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

“…Therefore, it is not surprising that several neurological disorders involve mutations in genes that encode chromatinbinding and/or -modifying enzymes. Examples include mutations in the gene encoding the chromatin-remodeling factor, ATRX, that causes a-thalassemia and X-linked mental retardation syndrome, as well as in genes encoding the histone H3K4me3-demethylase, JARID1C, that causes epilepsy X-linked mental retardation, the histone H3K9me1/2-methyltransferase complex, G9a/GLP (EHMT2/1), that results in a human mental retardation syndrome, and the histone acetyltransferase, CREB-binding protein, that causes Rubinstein-Taybi syndrome (Gibbons et al, 1995;Alarcon et al, 2004;Kleefstra et al, 2006;Tahiliani et al, 2007;Schaefer et al, 2009). A common theme of these disorders is that mutations in epigenetic regulators can alter chromatin structure and induce a broad spectrum of neurological and behavioral deficits.…”