Kabuki Syndrome 2

A number sign (#) is used with this entry because of evidence that Kabuki syndrome-2 (KABUK2) is caused by mutation in the KDM6A gene (300128) on chromosome Xp11.

Description

Kabuki syndrome is a congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids (reminiscent of the make-up of actors of Kabuki, a Japanese traditional theatrical form), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy (Niikawa et al., 1981).

For a discussion of genetic heterogeneity of Kabuki syndrome, see KABUK1 (147920).

Clinical Features

Lederer et al. (2012) studied 2 girls and a boy with Kabuki syndrome. The 2-year-old boy and 13-year-old girl had a typical Kabuki syndrome phenotype, including long palpebral fissures, lateral eversion of the lower eyelid, and moderate to severe intellectual disability; they also displayed long halluces. The facial features of the 10-year-old girl were not as classic, but she displayed many characteristics of the disorder, including lateral sparseness of the eyebrows, long eyelashes, strabismus, long palpebral fissures, large and prominent ears, persistent fetal fingertip pads, aortic coarctation, areolar fullness in infancy, and hirsutism; she also had mild developmental delay.

Diagnosis

Adam et al. (2019) reported consensus diagnostic criteria for Kabuki syndrome that were developed by an international group of experts after a systematic review of the literature. The authors proposed that a definitive diagnosis could be made in a patient at any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features at some point of life. Typical dysmorphic features included long palpebral fissures with eversion of the lateral third of the lower eyelid and 2 or more the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent, or cupped ears; and (4) persistent fingertip pads. Criteria for probable and possible diagnoses were also included.

Molecular Genetics

By array CGH analysis in 2 unrelated Belgian girls with Kabuki syndrome who were negative for mutation in the MLL2 gene (602113), Lederer et al. (2012) identified de novo Xp11.3 microdeletions, both of which contained part or all of the KDM6A gene (300128). In the 13-year-old girl, the deletion included KDM6A exons 21 through 29 and CXORF36 (300959), whereas in the 10-year-old girl, the deletion completely removed KDM6A, CXORF36, DUSP21 (300678) and FUNDC1 (300871). Sequencing of the KDM6A gene and targeted array CGH in a cohort of 22 MLL2-negative Kabuki syndrome patients revealed a de novo intragenic deletion in a 2-year-old Italian boy (300128.0001).

Miyake et al. (2013) analyzed the KDM6A gene in 32 patients with Kabuki syndrome who were negative for mutation in the MLL2 gene and identified nonsense mutations in 2 male patients and a 3-bp deletion in a female patient (300128.0002-300128.0004). The 3 mutation-positive patients all had severe developmental delay and intellectual disability, but the female patient had fewer dysmorphic features than the male patients, who displayed a more severe phenotype with multiple organ involvement. Peripheral leukocyte genomic DNA from the female patient showed a random pattern of X inactivation, in a 57:43 ratio. Miyake et al. (2013) suggested that the mutation type as well as X-inactivation pattern in affected organs in females may determine the severity of Kabuki syndrome.

Using direct sequencing, MLPA, and quantitative PCR, Micale et al. (2014) screened 303 patients with Kabuki syndrome and identified 4 KDM6A mutations, 3 of which were novel.

In 2 brothers with Kabuki syndrome, who were negative for mutation in the MLL2 gene, Lederer et al. (2014) identified a 4-bp deletion in the KDM6A gene (300128.0006). Their mother and maternal grandmother, who also carried the mutation, exhibited attenuated phenotypes. Lederer et al. (2014) reviewed the clinical features of all reported patients with KDM6A mutations and stated that the family reported by them represented the first instance of hereditary X-linked Kabuki syndrome.

Van Laarhoven et al. (2015) identified KMT2A mutations in 4 (10%) of 40 patients clinically diagnosed with Kabuki syndrome, including 2 patients with microdeletions that encompassed KDM6A.

Genotype/Phenotype Correlations

Miyake et al. (2013) screened 81 patients with Kabuki syndrome for mutations in the MLL2 and KDM6A genes and identified KDM6A mutations in 5 (6.2%) and MLL2 mutations in 50 (60.7%). Of the 5 KDM6A mutations, including 2 that were novel, 4 were protein-truncating and 1 was an in-frame deletion in the Jumonji C domain. High-arched eyebrows, short fifth fingers, and infantile hypotonia were less commonly seen in patients with KDM6A mutations than in those with MLL2 mutations. All of the patients with KDM6A mutations had short stature and postnatal growth retardation, compared with only half of the patients with MLL2 mutations. Among the 2 female patients with KDM6A mutations, one with an in-frame deletion (300128.0004) had a random X-inactivation pattern, whereas the other with a frameshift mutation (300128.0005) showed marked skewing.