Kleefstra Syndrome 2

A number sign (#) is used with this entry because of evidence that Kleefstra syndrome-2 (KLEFS2) is caused by heterozygous mutation in the KMT2C gene (606833) on chromosome 7q36.

Description

Kleefstra syndrome-2 is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, variable intellectual disability, and mild dysmorphic features (summary by Koemans et al., 2017).

For a discussion of genetic heterogeneity of Kleefstra syndrome, see KLEFS1 (610253).

Clinical Features

Kleefstra et al. (2012) reported a girl with Kleefstra syndrome-2. She had delayed psychomotor development and a total IQ of 35, walked independently at age 19 months but never developed speech, and developed progressive hyperactivity and aggressiveness. Dysmorphic features included midface hypoplasia, synophrys, upward slanting palpebral fissures, anteverted lower lip, childhood hypotonia, brachycephaly, coarse facies, and hypertelorism. At age 15 she had short stature and mild microcephaly.

Koemans et al. (2017) reported 5 unrelated patients, ranging in age from 7 to 31 years, with KLEFS2. All patients had delayed psychomotor development with mild to severe intellectual disability, speech delay, and features of autism with variable behavioral problems. Three patients had childhood hypotonia, 2 had seizures, and 3 had scoliosis or kyphosis. Dysmorphic facial features were variable, but included flattened midface, prominent eyebrows, everted lower lip, and thick ear helices.

Faundes et al. (2018) reported 3 unrelated patients with severe intellectual disability associated with de novo heterozygous mutations in the KMT2C gene. The patients had global developmental delay apparent in early infancy, with intellectual disability, mildly delayed walking, and poor or absent speech. They had poor overall growth with borderline small head circumference. Dysmorphic facial features were variable, but included downslanting palpebral fissures, ptosis, arched eyebrows, high palate, short nose, and deep-set eyes. One patient had a duplicated thumb, another had hydrocephalus with Dandy-Walker malformation and hypoplasia of the cerebellar vermis, and a third showed developmental regression.

Molecular Genetics

In 4 of 9 EHMT1 (607001) mutation-negative patients with core features of Kleefstra syndrome-1 (KLEFS1; 610253) but otherwise heterogeneous phenotypes, Kleefstra et al. (2012) identified mutations in 4 functionally related genes, KMT2C (606833.0001), MBD5 (611472), SMARCB1 (601607), and NR1I3 (603881). All these genes encode epigenetic regulators. The KMT2C mutation was a de novo heterozygous truncating mutation.

In 5 additional patients with KLEFS2, Koemans et al. (2017) identified 4 different de novo heterozygous frameshift or truncating mutations in the KMT2C gene (606833.0002-606833.0005). The fifth patient had a de novo heterozygous 203-kb intragenic deletion in the KMT2C gene. All mutations were predicted to result in a loss of function, but specific functional studies of the variants and studies of patient cells were not performed. Studies in Drosophila indicated a common molecular basis of the neuropathology associated with mutations in EHMT1 (KLEFS1) and KMT2C (KLEFS2) (see ANIMAL MODEL).

Animal Model

Koemans et al. (2017) found that specific knockdown of 'trr,' the Drosophila ortholog of KMT2C, in the mushroom body of the fly brain resulted in impaired short-term memory. Immunoprecipitation studies showed that trr normally localizes in the nucleus of the mushroom body, and that it binds to the promoter of many genes involved in neuronal processes in the fly head. Transcriptional profiling of pan-neuronal trr knockdown and G9a (the ortholog of EHMT1; 607001) null mutant fly heads identified many misregulated genes in both scenarios; these gene sets showed significant overlap and were associated with nearly identical gene ontology enrichments. There were many common indirect target genes and several common direct target genes, including those involved in regulation of synaptic plasticity. The findings delineated the molecular convergence between the KMT2 and EHMT protein families, which may contribute to a molecular network involved in neurodevelopment.