ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000010.10) (NC_000010.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22077973 Clayton-Smith et al (2011) identified de novo protein-truncating variants of KAT6B (lysine acetyltransferase 6B, formerly known as MYST4 and MORF) in 13/19 patients with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) using exome sequencing and Sanger sequencing. The SBBYS type of the blepharophimosis?intellectual disability syndrome group (Ohdo-like syndromes) is a multiple congenital malformation syndrome characterized by vertical narrowing and shortening of the palpebral fissures, ptosis, intellectual disability, hypothyroidism, hearing impairment, and dental anomalies. While genitopatellar syndrome (GPS) and SBBYS syndrome share some clinical features, such as intellectual disability, congenital heart defects, genital, and patellar anomalies, they can be clinically distinguished based on the presence or absence of specific skeletal, renal, and brain anomalies. In this study, all variants were clustered in the last exon (exon 18) of the gene.
22265014 Campeau et al (2012) identified de novo heterozygous truncating mutations in KAT6B in three patients with genitopatellar syndrome (GPS) using exome sequencing. Following exome study, by Sanger sequencing of KAT6B, they found similar sequence variants in three additional patients with GPS. This syndrome is a rare skeletal dysplasia combining hypoplastic or absent patellae, genital anomalies, craniofacial defects, and intellectual disability among other features. In this study, all five variants identified in six patients formed a cluster within the C-terminal acidic domain of KAT6B (2 nonsense variants and 3 frameshift insertions-deletions). None of the GPS variations have been shown to undergo-nonsense mediated decay and consequently truncated proteins are produced from these alleles. In contrast, variations leading to SBBYSS occur seemingly randomly throughout the gene, leading to nonsense-mediated decay, or occur more distally in the last exon than the GPS-associated cluster.
25424711 Gannon et al (2015) identified likely causative variants located in the last exon (exon 18) of KAT6B in 34/57 patients with SBBYSS or GPS. Of those where parental samples could be tested, all occurred de novo. Thirty out of 34 had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. In this study, a large chromosome deletion (about 2.5 Mb) encompassing KAT6B and 8 other genes was described in a patient with hypotonia, developmental delay, macrocephaly, blepharophimosis, short palpebral fissures and prominent epicanthic folds. The authors also noted that individuals with larger 10q22 deletions involving KAT6B (specifically those reported in PMID: 19844253) do not appear to have facial features suggestive of SBBYS.

Haploinsufficiency phenotype comments:

KAT6B-related disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker variant of Ohdo syndrome (Ohdo syndrome, SBBYS variant, or SBBYSS [Say-Barber-Biesecker-Young-Simpson syndrome]). Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities in males (cryptorchidism), and patellar hypoplasia/agenesis. Congenital heart defects, dental anomalies, hearing loss, and thyroid anomalies are common to both phenotypes. Also observed in GPS are flexion contractures of the hips and knees, club feet, agenesis of the corpus callosum with microcephaly, and hydronephrosis and/or multiple renal cysts. In SBBYS lower extremity joint stiffness, long thumbs/great toes, immobile mask-like face, blepharophimosis/ptosis, and lacrimal duct anomalies are observed (GeneReviews: All reported pathogenic variants are either nonsense or frameshift variations that cause a premature truncation of the protein. Of those where parental samples could be tested, all variants were de novo. Variations leading to GPS occur in the proximal portion of the last exon (5? portion of exon 18) and lead to the expression of a protein without an activation domain. Variations leading to SBBYSS occur either throughout the gene, leading to nonsense-mediated decay, or more distally in the last exon (3? portion of exon 18). It is possible that haploinsufficiency or loss of a function mediated by the C-terminal region causes the features common to both conditions. At this time, no focal deletions of KAT6B have been reported in the literature. Tzschach et al (2010) (PMID: 19844253) described four patients with 10q22 deletions encompassing KAT6B (MYST4). They had a mild phenotype with common features of hypotonia and developmental delay, especially in the area of speech. Facial features were nonspecific, though on scrutiny of the available photographs, blepharophimosis appeared to be a feature. Kraft et al. (2011) (PMID: 21804188) report an individual evaluated for Noonan syndrome-like features was found to have an apparently balanced de novo chromo?somal translocation t(10;13)(q22.3;q34). Genome-wide molecular karyotyping using an Affymetrix GeneChip Mapping 6.0 array excluded relevant copy number changes, suggesting a disruption of a gene at one of the translocation breakpoints associated with the phenotype. The authors mapped the translocation breakpoints using FISH analysis and long-range PCR and found the breakpoint in 10q22.3 to disrupt the KAT6B gene within intron 3 after the first coding exon. A 50% reduction of mRNA expression levels of this gene was confirmed by quantitative RT-PCR in the patient?s leucocytes. The breakpoint in 13q34 was not located within a gene previously associated with Noonan syndrome, and the TUBGCP3 gene, which is located 17.2-kb downstream, showed normal expression levels in the patient. Western blot analysis and gene structure prediction using GENSCAN showed no evidence of an aberrant KAT6B protein. Variation scanning of the entire coding sequence of the KAT6B gene was then performed in the patient to exclude a second hit, suggesting haploinsufficiency as a possible pathogenic mechanism. In summary: GPS. Known pathogenic variants causing GPS predict protein truncation and cluster in KAT6B exon 18, the last exon. Because pathogenic variants that predict truncation (nonsense, frameshift) that occur in the final exon of a gene typically do not result in nonsense-mediated decay of the mRNA, it is predicted that these KAT6B mutated alleles produce truncated proteins. SBBYSS. Known pathogenic variants causing SBBYSS occur mostly in exon 18 but some individuals ? often with an atypical SBBYSS phenotype ? were found to have pathogenic variants elsewhere in the gene. Nonsense/frameshift variants in exons other than 18 are predicted to lead to nonsense-mediated decay and lack of protein expression from that allele. Pathogenic variants in KAT6B exon 18 typically occur more distally than GPS-associated variants. Additional related articles: 1) Tzschach et al (2010). Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11. PMID: 19844253 2) Kraft et al (2011). Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice. PMID: 21804188 3) Simpson et al (2012). De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome. PMID: 22265017 4) Campeau et al (2012). The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms. PMID: 22715153 5) Szakszon et al (2013). De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say-Barber/Biesecker/Young-Simpson syndrome. PMID: 23436491 6) Lundsgaard et al (2017). De novo KAT6B Mutation Identified with Whole-Exome Sequencing in a Girl with Say-Barber/Biesecker/Young-Simpson Syndrome. PMID: 28232779

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there is no evidence that supports the triplosensitivity of KAT6B