Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: KAT6B
SNOMEDCT: 699298009, 702367005;
Cytogenetic location: 10q22.2 Genomic coordinates (GRCh38) : 10:74,824,936-75,032,624 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.2 | Genitopatellar syndrome | 606170 | Autosomal dominant | 3 |
| SBBYSS syndrome | 603736 | Autosomal dominant | 3 |
Champagne et al. (1999) identified and characterized monocytic leukemia zinc finger protein-related factor (MORF), a novel human histone acetyltransferase. MORF is a 1,781-residue protein that is ubiquitously expressed in adult human tissues. MORF also contains a strong transcriptional repression domain at its N terminus and a highly potent activation domain at its C terminus, and may be involved in both positive and negative regulation of transcription.
Using immunohistochemistry on mice of various developmental ages, Campeau et al. (2012) demonstrated expression of Myst4 in the telencephalic vesicles, trigeminal ganglion, spinal cord, dorsal root ganglia, digestive tract, pancreas, liver, and ribs of developing embryo; after birth, it is strongly expressed in the diaphysis of the long bones, the kidney, and the patella, among other organs.
MORF/CBP Fusion Gene
Panagopoulos et al. (2001) reported a novel t(10;16)(q22;p13) chromosomal translocation in a childhood acute myelogenous leukemia (AML-M5a) leading to a MORF-CBP (600140) chimera. RT-PCR experiments yielded in-frame MORF-CBP and CBP-MORF fusion transcripts. Genomic analyses revealed that the breaks were close to Alu elements in intron 16 of MORF and intron 2 of CBP and that duplications had occurred near the breakpoints. The authors constructed an exon/intron map of the MORF gene. The MORF-CBP protein retained the zinc fingers, 2 nuclear localization signals, the histone acetyltransferase (HAT) domain, a portion of the acidic domain of MORF, and the CBP protein downstream of codon 29. The part of CBP encoding the RARA-binding domain, the CREB-binding domain, the 3 cys/his-rich regions, the bromodomain, the HAT domain and the glu-rich domains was present. In the reciprocal CBP-MORF, part of the acidic domain, and the C-terminal ser- and met-rich regions of MORF may be driven by the CBP promoter.
Champagne et al. (1999) mapped the MORF gene to chromosome 10q22 by FISH.
SBBYSS Syndrome and Genitopatellar Syndrome
Clayton-Smith et al. (2011) studied a cohort of 19 individuals with a presumed diagnosis of the Ohdo syndrome SBBYS variant (SBBYSS; 603736). Twelve individuals were considered to have typical features of the syndrome, 2 had suggestive but milder features, and 5 were classified as atypical. By whole-exome sequencing in 4 individuals with typical features, Clayton-Smith et al. (2011) identified heterozygous mutations in the KAT6B gene: a nonsense mutation (E1357X; 605880.0004) in individual 4, a 1-bp duplication (605880.0001) in individual 1, and a 4-bp duplication (605880.0002) in individual 2. Subsequently, all 19 individuals with an SBBYSS or an SBBYSS-like phenotype were sequenced for the entire KAT6B coding region by classic Sanger sequencing. Truncating mutations in exon 18 of the KAT6B gene were confirmed in 12 individuals, and individual 3 was found to have a heterozygous frameshift mutation in exon 15 (605880.0003), which had not been detected on whole-exome sequencing. When parental samples were available, the mutations were shown to have occurred de novo. Clayton-Smith et al. (2011) suggested that mutations of protein-protein interaction domains in exon 18 result in a more complex phenotype than the phenotype due to simple haploinsufficiency of KAT6B and raised the possibility that exon 18 mutations are activating or have a dominant-negative effect.
In 6 patients with genitopatellar syndrome (GTPTS; 606170), Campeau et al. (2012) identified 5 different heterozygous de novo truncating mutations in exon 18 of the KAT6B gene (605880.0005-605880.0009), all of which were predicted to result in loss of the highly conserved transcription activation domain. Campeau et al. (2012) noted that SBBYSS, also caused by mutation in KAT6B, is a disorder with features overlapping those of genitopatellar syndrome, but with clinical differences.
Simpson et al. (2012) identified mutations in the KAT6B gene in 5 unrelated patients with genitopatellar syndrome (see, e.g., 605880.0006 and 605880.0010); they stated that the form of Ohdo syndrome (SBBYSS) in which mutations in KAT6B had been found is phenotypically distinct from genitopatellar syndrome.
In 2 children with clinical features of SBBYSS, including a 4-year-old girl previously reported by Szakszon et al. (2011), Szakszon et al. (2013) identified different de novo truncating mutations in the distal region of exon 18 of the KAT6B gene (605880.0011-605880.0012).
Yates et al. (2019) identified a novel heterozygous splicing mutation in intron 5 of the KAT6B gene (605880.0013) in affected members of a family with SBBYSS. The mutation was found by exome sequencing and confirmed by Sanger sequencing.
Szakszon et al. (2013) noted that truncating mutations of KAT6B exon 18 between positions c.3018 and c.3892 had been shown to cause GTPTS, whereas truncating mutations distal to position c.4069 in the same exon cause SBBYSS (with one exception, a c.4360_4368delins mutation in a patient with GTPTS; see 605880.0005). They stated that their finding of truncating mutations of KAT6B exon 18 at positions c.5064_5071 (605880.0011) and c.5389 (605880.0012) in patients with SBBYSS confirmed this genotype-phenotype correlation.
Lonardo et al. (2019) reviewed the issue of whether SBBYSS and GTPTS should be considered distinct disorders or variations of the same disorder, given that they are both caused by pathogenic variants in the KAT6B gene. The authors noted that patients with mutations that occur more proximally, which are subject to nonsense-mediated decay (NMD), are more likely to present with a milder SBBYSS phenotype caused by haploinsufficiency. Variants not subject to NMD that affect critical binding sites of KAT6B are more likely to cause a more severe GTPTS phenotype. Variants that occur more distally and escape NMD but do not interfere with critical KAT6B binding sites are more likely to cause the SBBYSS phenotype rather than GTPTS.
Clayton-Smith et al. (2011) examined mice carrying a gene trap insertion in the mouse ortholog Kat6b (Qkf/Myst4/Morf) that produces approximately 5% of the normal amount of Kat6b mRNA. The Qkf gt/gt hypomorphic mutant displayed a number of defects that mirror SBBYSS syndrome, although the phenotype in the mice is milder. Mice are of normal size at birth but fail to thrive and have brain developmental defects as well as craniofacial defects. Observed abnormalities include short and narrow palpebral fissures, low set ears, and malocclusion. Qkf mRNA is strongly expressed in the eyelids and teeth primordia during development. Similar to individuals with SBBYSS, the Qkf gt/gt mice have long, slender feet and disproportionately long first digits.
By whole-exome sequencing in a patient (individual 1) with typical features of SBBYSS (603736), previously reported by Clayton-Smith et al. (1994), Clayton-Smith et al. (2011) identified a 1-bp duplication at nucleotide 4405 in exon 18 of the KAT6B gene, which resulted in a frameshift (Ser1469PhefsTer18).
By whole-exome sequencing in a patient (individual 2) with typical features of SBBYSS (603736), Clayton-Smith et al. (2011) identified a 4-bp duplication at nucleotide 5370 in exon 18 of the KAT6B gene, which resulted in a frameshift (Ile1792GlnfsTer12).
By Sanger sequencing in a patient (individual 3) with typical SBBYSS (603736), Clayton-Smith et al. (2011) identified a 1-bp deletion at nucleotide 3018 in exon 15 of the KAT6B gene, which resulted in a frameshift (Glu1007ArgfsTer5). The mutation was not initially detected on whole-exome sequencing. The parents did not have the mutation. The patient also had a 1q21 duplication, which the authors considered to be incidental.
By whole-exome sequencing in a patient (individual 4) with typical features of SBBYSS (603736), previously described by Day et al. (2008), Clayton-Smith et al. (2011) identified a heterozygous 4069G-T transversion in exon 18 of the KAT6B gene, resulting in a glu1357-to-ter (E1357X) substitution. The parents did not have the mutation.
In a male patient with genitopatellar syndrome (GTPTS; 606170), originally reported by Abdul-Rahman et al. (2006) ('patient 2'), Campeau et al. (2012) identified heterozygosity for a de novo deletion/insertion (4360_4368delinsAAAAACCAAAA) in exon 18 of the KAT6B gene, predicted to result in premature termination and loss of the highly conserved transcription activation domain. The mutation was not found in the patient's unaffected parents or in the Exome Variant Server.
In an unrelated 7-month-old girl and 3-month-old boy with genitopatellar syndrome (606170), Simpson et al. (2012) identified heterozygosity for a 4-bp deletion (3768_3771delTCTA) in the KAT6B gene, resulting in a frameshift and premature termination (Lys1258GlyfsTer13). The mutation was not present in their unaffected parents, in the 1000 Genomes Project, or in 600 control exome profiles. Quantitative assessment of global H3/H4 acetylation of extracted histones in primary skin fibroblasts from the infant girl demonstrated a significant reduction in H3 and H4 acetylation compared to control fibroblasts.
In 2 unrelated male patients with genitopatellar syndrome (606170), 1 of whom was originally reported by Lifchez et al. (2003), Campeau et al. (2012) identified heterozygosity for a de novo 4-bp deletion, which they stated as 3769_3772delTCTA, in exon 18 of the KAT6B gene, predicted to result in premature termination and loss of the highly conserved transcription activation domain (Lys1258GlyfsTer13). The mutation was not found in the patients' unaffected parents or in the Exome Variant Server.
In a female patient with genitopatellar syndrome (606170), Campeau et al. (2012) identified heterozygosity for a de novo 2-bp deletion (3788_3789delAA) in exon 18 of the KAT6B gene, predicted to result in premature termination and loss of the highly conserved transcription activation domain (Lys1263ArgfsTer7). The mutation was not found in the patients' unaffected parents or in the Exome Variant Server.
In an African American girl with genitopatellar syndrome (606170), originally reported by Abdul-Rahman et al. (2006), Campeau et al. (2012) identified heterozygosity for a 3892G-T transversion in exon 18 of the KAT6B gene, predicted to result in premature termination and loss of the highly conserved transcription activation domain. DNA from the patient's parents was unavailable; however, the mutation was not found in the Exome Variant Server.
In a female patient with genitopatellar syndrome (606170), originally reported by Lammer and Abrams (2002), Campeau et al. (2012) identified heterozygosity for a de novo 3802G-T transversion in exon 18 of the KAT6B gene, predicted to result in premature termination and loss of the highly conserved transcription activation domain (G1268X). The mutation was not found in the patient's unaffected parents or in the Exome Variant Server.
In a female patient with genitopatellar syndrome (606170), originally reported by Reardon (2002), Simpson et al. (2012) identified heterozygosity for a de novo 16-bp deletion (3680_3695del) in exon 18 of the KAT6B gene, resulting in a frameshift (Asp1227GlufsTer11). The mutation was not found in her unaffected parents, in the 1000 Genomes Project, or in 600 control exome profiles.
In a child of Sicilian ancestry with SBBYSS (603736), Szakszon et al. (2013) identified a heterozygous, de novo, complex insertion/deletion mutation, c.5064_5071delTACTATGGinsCACA, in exon 18 of the KAT6B gene, leading to a net loss of 4 bp, a frameshift, and a premature stop codon (Met1690GlufsTer24).
By Sanger sequencing in a patient (individual 13) with typical SBBYSS (603736), Clayton-Smith et al. (2011) identified a heterozygous de novo c.5389C-T transition in exon 18 of the KAT6B gene, resulting in an arg1797-to-ter (R1797X) substitution. The parents did not have the mutation.
In a child of Hungarian ancestry with typical SBBYSS, previously reported by Szakszon et al. (2011), Szakszon et al. (2013) identified de novo heterozygosity for the same R2797X mutation.
By exome sequencing in affected members of a family with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; 603736), Yates et al. (2019) identified a heterozygous splice site mutation (c.847-2A-G) in intron 5 of the KAT6B gene, predicted to disrupt the exon 6 splice acceptor site. The finding was confirmed in the family by Sanger sequencing. The patients had a milder dysmorphic and impaired intellectual development phenotype than typically seen in SBBYSS. Yates et al. (2019) proposed that proximal pathogenic variants, which are more likely to result in nonsense-mediated decay (NMD), may be associated with a milder phenotype than distal pathogenic variants, which escape NMD and result in a more severe phenotype. The authors also noted variability of the phenotype within the family, which they suggested could be attributable to leaky splicing.
Abdul-Rahman, O. A., La, T. H., Kwan, A., Schlaubitz, S., Barsh, G. S., Enns, G. M., Hudgins, L. Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4. Am. J. Med. Genet. 140A: 1567-1572, 2006. [PubMed: 16761293] [Full Text: https://doi.org/10.1002/ajmg.a.31258]
Campeau, P. M., Kim, J. C., Lu, J. T., Schwartzentruber, J. A., Abdul-Rahman, O. A., Schlaubitz, S., Murdock, D. M., Jiang, M.-M., Lammer, E. J., Enns, G. M., Rhead, W. J., Rowland, J., and 9 others. Mutations in KAT6B, encoding a histone acetyltransferase, cause genitopatellar syndrome. Am. J. Hum. Genet. 90: 282-289, 2012. [PubMed: 22265014] [Full Text: https://doi.org/10.1016/j.ajhg.2011.11.023]
Champagne, N., Bertos, N. R., Pelletier, N., Wang, A. H., Vezmar, M., Yang,Y., Heng, H. H., Yang, X. J. Identification of a human histone acetyltransferase related to monocytic leukemia zinc finger protein. J. Biol. Chem. 274: 28528-28536, 1999. [PubMed: 10497217] [Full Text: https://doi.org/10.1074/jbc.274.40.28528]
Clayton-Smith, J., Krajewska-Walasek, M., Fryer, A., Donnai, D. Ohdo-like blepharophimosis syndrome with distinctive facies, neonatal hypotonia, mental retardation and hypoplastic teeth. Clin. Dysmorph. 3: 115-120, 1994. [PubMed: 8055130]
Clayton-Smith, J., O'Sullivan, J., Daly, S., Bhaskar, S., Day, R., Anderson, B., Voss, A. K., Thomas, T., Biesecker, L. G., Smith, P., Fryer, A., Chandler, K. E., and 13 others. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. Am. J. Hum. Genet. 89: 675-681, 2011. [PubMed: 22077973] [Full Text: https://doi.org/10.1016/j.ajhg.2011.10.008]
Day, R., Beckett, B., Donnai, D., Fryer, A., Heidenblad, M., Howard, P., Kerr, B., Mansour, S., Maye, U., McKee, S., Mohammed, S., Sweeney, E., Tassabehji, M., de Vries, B. B. A., Clayton-Smith, J. A clinical and genetic study of the Say/Barber/Biesecker/Young-Simpson type of Ohdo syndrome. Clin. Genet. 74: 434-444, 2008. [PubMed: 18798845] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01087.x]
Lammer, E. J., Abrams, L. Genitopatellar syndrome: delineating the anomalies of female genitalia. Am. J. Med. Genet. 111: 316-318, 2002. [PubMed: 12210330] [Full Text: https://doi.org/10.1002/ajmg.10582]
Lifchez, C. A., Rhead, W. J., Leuthner, S. R., Lubinsky, M. S. Genitopatellar syndrome: expanding the phenotype. Am. J. Med. Genet. 122A: 80-83, 2003. [PubMed: 12949978] [Full Text: https://doi.org/10.1002/ajmg.a.20268]
Lonardo, F., Lonardo, M. S., Acquaviva, F., Della Monica, M., Scarano, F., Scarano, G. Say-Barber-Biesecker-Young-Simpson syndrome and genitopatellar syndrome: lumping or splitting? Clin. Genet. 95: 253-261, 2019. [PubMed: 28857140] [Full Text: https://doi.org/10.1111/cge.13127]
Panagopoulos, I., Fioretos, T., Isaksson, M., Samuelsson, U., Billstrom, R., Strombeck, B., Mitelman, F., Johansson, B. Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Hum. Molec. Genet. 10: 395-404, 2001. [PubMed: 11157802] [Full Text: https://doi.org/10.1093/hmg/10.4.395]
Reardon, W. Genitopatellar syndrome: a recognizable phenotype. Am. J. Med. Genet. 111: 313-315, 2002. [PubMed: 12210329] [Full Text: https://doi.org/10.1002/ajmg.10590]
Simpson, M. A., Deshpande, C., Dafou, D., Vissers, L. E. L. M., Woollard, W. J., Holder, S. E., Gillessen-Kaesbach, G., Derks, R., White, S. M., Cohen-Snuijf, R., Kant, S. G., Hoefsloot, L. H., Reardon, W., Brunner, H. G., Bongers, E. M. H. F., Trembath, R. C. De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause genitopatellar syndrome. Am. J. Hum. Genet. 90: 290-294, 2012. [PubMed: 22265017] [Full Text: https://doi.org/10.1016/j.ajhg.2011.11.024]
Szakszon, K., Berenyi, E., Jakab, A., Bessenyei, B., Balogh, E., Kobling, T., Szilvassy, J., Knegt, A. C., Olah, E. Blepharophimosis mental retardation syndrome Say-Barber/Biesecker/Young-Simpson type: new findings with neuroimaging. Am. J. Med. Genet. 155A: 634-637, 2011. [PubMed: 21344633] [Full Text: https://doi.org/10.1002/ajmg.a.33837]
Szakszon, K., Salpietro, C., Kakar, N., Knegt, A. C., Olah, E., Dallapiccola, B., Borck, G. De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say-Barber/Biesecker/Young-Simpson syndrome. Am. J. Med. Genet. 161A: 884-888, 2013. [PubMed: 23436491] [Full Text: https://doi.org/10.1002/ajmg.a.35848]
Yates, T. M., Langley, C. L. M., DDD Study, Grozeva, D., Raymond, F. L., Johnson, D. S. Novel KAT6B proximal familial variant expands genotypic and phenotypic spectrum. (Letter) Clin. Genet. 95: 334-335, 2019. [PubMed: 30353918] [Full Text: https://doi.org/10.1111/cge.13456]