Kleefstra Syndrome 1

A number sign (#) is used with this entry because of evidence that Kleefstra syndrome-1 (KLEFS1) is caused by heterozygous mutation in the EHMT1 gene (607001), which is located within the region of the chromosome 9q34.3 deletion syndrome.

Description

Submicroscopic subtelomeric deletions of chromosome 9q are associated with a recognizable mental retardation syndrome (Harada et al., 2004; Iwakoshi et al., 2004; Stewart et al., 2004; Neas et al., 2005). Common features in patients with 9q subtelomeric deletion syndrome are severe mental retardation, hypotonia, brachy(micro)cephaly, epileptic seizures, flat face with hypertelorism, synophrys, anteverted nares, everted lower lip, carp mouth with macroglossia, and heart defects.

Genetic Heterogeneity of Kleefstra Syndrome

KLEFS2 (617768) is caused by mutation in the KMT2C gene (606833) on chromosome 7q36.

Clinical Features

Kleefstra et al. (2009) reported 16 patients with 9q deletions identified by routine chromosome testing or whole genome array analysis and 6 additional patients with intragenic EHMT1 mutations and normal chromosome studies. All patients showed the core phenotype of the deletion syndrome, including mental retardation without speech development, hypotonia, and characteristic facial features. Facial features included microcephaly, brachycephaly, hypertelorism, synophrys, midface hypoplasia, protruding tongue, eversion of the lower lip, and prognathism. Birth weight was often increased compared to normal and many had childhood obesity. Motor function was delayed, but all individuals were able to walk between 2 and 3 years, except 1 patient. Eight patients had congenital heart defects, including atrial or ventricular septal defects, tetralogy of Fallot, aortic coarctation, bicuspid aortic valve, and pulmonic stenosis. Seven patients had seizures. Less common and variable features included micropenis, cryptorchidism, vesicoureteral reflux, tracheo-/bronchomalacia, and gastroesophageal reflux. Brain imaging was generally normal, but some showed dilated ventricles, abnormal myelination, or other mild changes. Five patients that reached adult age showed abrupt behavioral changes around adolescence with some later recovery. Abnormalities included apathy, aggressive periods, psychosis, autistic features, catatonia, bipolar mood disorder, and regression in daily function and cognitive abilities. There were no apparent genotype/phenotype correlations with the size of the deletion or between those with deletions and those with mutations. Kleefstra et al. (2009) concluded that haploinsufficiency for the EHMT1 gene is responsible for the main phenotypic features.

Verhoeven et al. (2011) reviewed the clinical histories of 3 unrelated women, aged 43, 33, and 19 years, with Kleefstra syndrome. Two had a heterozygous intragenic loss-of-function mutation in the EHMT1 gene and the third had a heterozygous 9q34.3 microdeletion encompassing the EHMT1 gene. All had delayed psychomotor development since early childhood, and showed progressive regression in behavior. The oldest patient showed a decline in global functioning beginning at age 38 years and necessitating institutionalization. The other 2 patients showed onset of behavioral regression around puberty. On physical examination as adults, all showed the characteristic facial features of Kleefstra syndrome, as well as rigid flexion of the arms, legs, hands, and feet and slow motor functioning. Abnormal behaviors included impulsivity, poor speech, repetitive behaviors, restricted social interactions, apathy, and poor response to external stimuli. All were severely disabled. The 2 older patients showed signs of catatonia, and both had white matter abnormalities on brain imaging. All patients had a disturbed sleep-wake pattern. The findings were consistent with a neurodegenerative or regressive neurologic process.

Inheritance

Most cases of Kleefstra syndrome are caused by de novo mutations. However, Willemsen et al. (2011) reported 2 unrelated families in which affected children inherited an interstitial 9q34.3 deletion from a mildly affected mother who was somatically mosaic for the deletion. Features in the 2 mothers included learning difficulties and mild facial dysmorphisms such as hypoplastic midface, upslanting palpebral fissures, depressed nasal root, and anteverted nares. The first family carried a 233-kb deletion with a proximal breakpoint in intron 4 of the EHMT1 gene and a distal breakpoint in the CACNA1B gene (601012). The second family carried a 179- to 210-kb deletion with a proximal breakpoint upstream of the EHMT1 gene and eliminating at least 5 exons of the EHMT1 gene. Willemsen et al. (2011) noted the implications for genetic counseling and emphasized that multiplex ligation-dependent probe amplification (MLPA) may be necessary to detect mosaicism.

Cytogenetics

Although the phenotype of this recognizable entity was considered to be a contiguous gene deletion syndrome, evidence indicated that the core phenotype was due to haploinsufficiency of one gene, EHMT1, which encodes chromatin histone methyltransferase-1 (607001). Kleefstra et al. (2006) characterized the breakpoints in a female with a balanced translocation t(X;9)(p11.23;q34.3) and found that the chromosome 9 breakpoint disrupted the EHMT1 gene in intron 9. The patient presented typical features of 9q subtelomeric deletion syndrome, including severe mental retardation, facial dysmorphism, cardiac anomaly, seizures, hearing loss, and behavioral problems.

Kleefstra et al. (2009) examined the deletion sizes in 16 patients found to have 9q deletions by routine subtelomeric chromosome testing. Initially, 7 patients were identified by FISH, 7 by multiplex ligation-dependent probe amplification (MLPA), and 2 by microarray analysis. The deletion breakpoints and sizes were heterogeneous: the most common deletion, found in 6 patients, ranged from 700 kb to 1.3 Mb. The largest deletion was 3.1 Mb and extended from the CACNA1B gene (601012) to the OLFM1 gene (605366). The smallest deletion was 40 kb, comprising exons 11 to 25 of the EHMT1 gene, exclusively. The patient with the largest deletion had several congenital abnormalities, such as micropenis, undescended testes, vesicoureteral reflux, and aortic coarctation, but the authors noted that these features have also been observed in patients with smaller deletions.

Molecular Genetics

Kleefstra et al. (2006) identified 2 heterozygous de novo mutations, a nonsense mutation and a frameshift mutation, in the EHMT1 gene in patients with a typical 9q- phenotype (607001.0001-607001.0002). Of the 5 patients they reported, Kleefstra et al. (2006) remarked that the 2 with mutations were as severely affected as the 3 with deletions, and the patients with a typical 9q deletion were as severely affected as those described in the literature.

In 6 of 24 patients with a clinical phenotype consistent with 9q deletion syndrome who had normal chromosome studies, Kleefstra et al. (2009) identified 6 different intragenic mutations in the EHMT1 gene (e.g., C1042Y, 607001.0003; R260X, 607001.0004). There were 2 nonsense mutations, a deletion, 2 splice site mutations, and 1 missense mutation in a highly conserved residue. A comparison of the phenotype between these 6 patients and 16 additional patients with larger deletions of 9q showed no genotype/phenotype correlations. Kleefstra et al. (2009) concluded that haploinsufficiency for EHMT1 is the basis for the phenotypic features in this disorder.

Yatsenko et al. (2009) characterized genomic rearrangements in 28 unrelated patients with 9q34.3 subtelomeric deletions. Four distinct categories were delineated: terminal deletions, interstitial deletions, derivative chromosomes, and complex rearrangements. Each kind results in haploinsufficiency of the EHMT1 gene and a characteristic phenotype. Seven (25%) patients had de novo interstitial deletions, 7 (25%) were found with derivative chromosomes or complex rearrangements, and 14 (50%) had bona fide terminal deletions. Interspersed repetitive elements (including Alu, LINE, LTR, and STR) were frequently observed at the breakpoints. Repetitive elements may play an important role by providing substrates with a specific DNA secondary structure that stabilizes broken chromosomes or assist in either DNA double-strand break repair or repair of single double-strand DNA ends generated by collapsed forks. Sequence analysis of the breakpoint junctions suggested that subtelomeric deletions may be stabilized by both homologous and nonhomologous recombination mechanisms, through a telomere-capture event, de novo telomere synthesis, or multistep breakage-fusion-bridge cycles.

Genetic Heterogeneity

Among 4 of 9 EHMT1 mutation-negative patients with core phenotypic features of Kleefstra syndrome but with phenotypic heterogeneity, referred to as Kleefstra syndrome spectrum (KSS), Kleefstra et al. (2012) identified de novo mutations in 4 genes, MBD5 (611472), MLL3 (606833), SMARCB1 (601607), and NR1I3 (603881), that encode epigenetic regulators. Shared phenotypic features among these patients include intellectual disability and childhood hypotonia, present in all, and behavioral problems, synophrys, and midface hypoplasia, present in a majority. Otherwise the phenotypes were quite variable. Using Drosophila, Kleefstra et al. (2012) demonstrated that MBD5, MLL3, and NR1I3, cooperate with EHMT1; SMARCB1 was known to interact directly with MLL3.