ORPHA: 2322; DO: 0060473;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.3 | Kabuki syndrome 2 | 300867 | X-linked dominant | 3 | KDM6A | 300128 |
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.
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).
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.
Faundes et al. (2021) analyzed clinical data in 80 patients with KABUK2. The most frequent neonatal finding was feeding problems, and hypoglycemia was described in 56.4% of neonates. Motor delay was reported in 95% of patients; 73.8% of patients achieved independent walking. Speech delay was reported in 91.5%; 71.4% of patients achieved speech. Impaired intellectual development was reported in 93% of patients, with more than half having severe impairment. The most frequent congenital malformations involved the cardiovascular system (49.2%), with atrial septal defects and ventricular defects the most common malformations. Genitourinary anomalies were reported in 26.4%, with horseshoe kidney the most common anomaly. Palate and dental anomalies were seen in 64.2% and 60%, respectively. Hearing loss affected 30.8%, and 31.3% had strabismus. Other clinical findings in this cohort included recurrent infections, hyperinsulinism, seizures, joint hypermobility, and ectodermal abnormalities. Typical Kabuki syndrome facial features were seen in 63.7% of patients. A comparison of males and females in this cohort showed that males were born earlier and had shorter birth lengths; fewer males could walk independently or developed speech; and males had a higher frequency of severely impaired intellectual development and a higher frequency of gastrointestinal problems.
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.
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.
Faundes et al. (2021) analyzed molecular data on 36 newly reported and 49 previously reported patients with heterozygous or hemizygous mutations in the KDM6A gene. Sixty-six KDM6A mutations were identified in 78 families, including 50 premature termination variants (PTV) in 62 patients from 59 families and 16 protein-altering variants (PAVs) in 23 patients from 19 families. The PTVs were all classified as pathogenic. Fifteen PTVs were nonsense mutations, 14 affected canonical splice sites, 12 were frameshift mutations, 8 were gross deletions, and 1 resulted from a chromosome translocation disrupting the KDM6A gene. In 42 patients, including 13 males and 29 females, the KDM6A PTVs were de novo, and in 6 patients the mutations were inherited from the mother. Of the 16 PAVs, 12 were classified as pathogenic or likely pathogenic, 3 as variants of uncertain significance, and 1 as likely benign. Thirteen of the PAVs were missense, 2 were in-frame deletions, and 1 was an indel. Eight PAVs, in 2 males and 6 females, were de novo. Ten patients inherited the PAV from their mother, and 1 patient inherited the mutation from her father. Inheritance of the PAVs was not known in 4 patients.
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.
Faundes et al. (2021) analyzed molecular and clinical data in 80 patients with heterozygous or hemizygous mutations in the KDM6A gene. Patients with protein-altering variants (PAVs) had shorter birth lengths compared to patients with protein termination variants (PTVs). Patients with PTVs had more impaired intellectual development (97.6% vs 80%) and a higher frequency of central nervous system anomalies (71.4% vs 28.6%) compared to patients with PAVs, although the difference did not reach statistical significance. Faundes et al. (2021) concluded that individuals with PTVs overall have a more severe phenotype, and the phenotypes of patients with PAVs are more variable.
Adam, M. P., Banka, S., Bjornsson, H. T., Bodamer, O., Chudley, A. E., Harris, J., Kawame, H., Lanpher, B. C., Lindsley, A. W., Merla, G., Miyake, N., Okamoto, N., Stumpel, C. T., Niikawa, N., the Kabuki Syndrome Medical Advisory Board. Kabuki syndrome: international consensus diagnostic criteria. J. Med. Genet. 56: 89-95, 2019. [PubMed: 30514738] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105625]
Faundes, V., Goh, S., Akilapa, R., Bezuidenhout H., Bjornsson, H. T., Bradley, L., Brady, A. F., Brischoux-Boucher, E., Brunner, H., Bulk, S., Canham, N., Cody, D., and 32 others. Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2. Genet. Med. 23: 1202-1210, 2021. [PubMed: 33674768] [Full Text: https://doi.org/10.1038/s41436-021-01119-8]
Lederer, D., Grisart, B., Digilio, M. C., Benoit, V., Crespin, M., Ghariani, S. C., Maystadt, I., Dallapiccola, B., Verellen-Dumoulin, C. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am. J. Hum. Genet. 90: 119-124, 2012. [PubMed: 22197486] [Full Text: https://doi.org/10.1016/j.ajhg.2011.11.021]
Lederer, D., Shears, D., Benoit, V., Verellen-Dumoulin, C., Maystadt, I. A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A. Am. J. Med. Genet. 164A: 1289-1292, 2014. [PubMed: 24664873] [Full Text: https://doi.org/10.1002/ajmg.a.36442]
Micale, L., Augello, B., Maffeo, C., Selicorni, A., Zucchetti, F., Fusco, C., De Nittis, P., Pellico, M. T., Mandriani, B., Fischetto, R., Boccone, L., Silengo, M., and 27 others. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum. Mutat. 35: 841-850, 2014. [PubMed: 24633898] [Full Text: https://doi.org/10.1002/humu.22547]
Miyake, N., Koshimizu, E., Okamoto, N., Mizuno, S., Ogata, T., Nagai, T., Kosho, T., Ohashi, H., Kato, M., Sasaki, G., Mabe, H., Watanabe, Y., and 31 others. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am. J. Med. Genet. 161A: 2234-2243, 2013. [PubMed: 23913813] [Full Text: https://doi.org/10.1002/ajmg.a.36072]
Miyake, N., Mizuno, S., Okamoto, N., Ohashi, H., Shiina, M., Ogata, K., Tsurusaki, Y., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. KDM6A point mutations cause Kabuki syndrome. Hum. Mutat. 34: 108-110, 2013. [PubMed: 23076834] [Full Text: https://doi.org/10.1002/humu.22229]
Niikawa, N., Matsuura, N., Fukushima, Y., Ohsawa, T., Kajii, T. Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J. Pediat. 99: 565-569, 1981. [PubMed: 7277096] [Full Text: https://doi.org/10.1016/s0022-3476(81)80255-7]
Van Laarhoven, P. M., Neitzel, L. R., Quintana, A. M., Geiger, E. A., Zackai, E. H., Clouthier, D. E., Artinger, K. B., Ming, J. E., Shaikh, T. H. Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development. Hum. Molec. Genet. 24: 4443-4453, 2015. [PubMed: 25972376] [Full Text: https://doi.org/10.1093/hmg/ddv180]