Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome

Genetic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, School of Biomedicine, University of Manchester, Manchester M13 9WL, UK.
The American Journal of Human Genetics (Impact Factor: 10.93). 11/2011; 89(5):675-81. DOI: 10.1016/j.ajhg.2011.10.008
Source: PubMed


Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.

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    • "In mice, reduced expression of KAT6B results in developmental anomalies of the skeleton and brain [50]. In humans, KAT6B has been associated with Ohdo syndrome for which symptoms include skeletal, facial, cardiac and dental abnormalities [51] and with genitopatellar syndrome [52], a skeletal dysplasia. In mice, mutations in the KCNMA1 gene cause cerebellar dysfunction, abnormal locomotion, and deficient motor coordination [53]. "
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    ABSTRACT: Background The present availability of sequence data gives new opportunities to narrow down from QTL (quantitative trait locus) regions to causative mutations. Our objective was to decrease the number of candidate causative mutations in a QTL region. For this, a concordance analysis was applied for a leg conformation trait in dairy cattle. Several QTL were detected for which the QTL status (homozygous or heterozygous for the QTL) was inferred for each individual. Subsequently, the inferred QTL status was used in a concordance analysis to reduce the number of candidate mutations. Methods Twenty QTL for rear leg set side view were mapped using Bayes C. Marker effects estimated during QTL mapping were used to infer the QTL status for each individual. Subsequently, polymorphisms present in the QTL regions were extracted from the whole-genome sequences of 71 Holstein bulls. Only polymorphisms for which the status was concordant with the QTL status were kept as candidate causative mutations. Results QTL status could be inferred for 15 of the 20 QTL. The number of concordant polymorphisms differed between QTL and depended on the number of QTL statuses that could be inferred and the linkage disequilibrium in the QTL region. For some QTL, the concordance analysis was efficient and narrowed down to a limited number of candidate mutations located in one or two genes, while for other QTL a large number of genes contained concordant polymorphisms. Conclusions For regions for which the concordance analysis could be performed, we were able to reduce the number of candidate mutations. For part of the QTL, the concordant analyses narrowed QTL regions down to a limited number of genes, of which some are known for their role in limb or skeletal development in humans and mice. Mutations in these genes are good candidates for QTN (quantitative trait nucleotides) influencing rear leg set side view.
    Full-text · Article · May 2014 · Genetics Selection Evolution
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    • "Asterisk denotes that the human homologue of QKF is referred to as KAT6B and the Drosophila homologue as enok. Based on the NCBI database and Callebaut and Mornon 2012; Chinenov 2002; Doi et al. 2006; Dutnall et al. 1998; Kalkhoven 2004; Marmorstein and Roth 2001; Voss and Thomas 2011; Wassarman and Sauer 2001 Yang 2011), it will not be discussed here. For an in-depth description of neural development, readers are referred to the following excellent reviews and textbooks (Gilbert 2003; Gotz and Huttner 2005; Greene and Copp 2009; Price et al. 2011; Stiles and Jernigan 2010). "
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    ABSTRACT: The human brain is a highly specialized organ containing nearly 170 billion cells with specific functions. Development of the brain requires adequate proliferation, proper cell migration, differentiation and maturation of progenitors. This is in turn dependent on spatial and temporal coordination of gene transcription, which requires the integration of both cell intrinsic and environmental factors. Histone acetyltransferases (HATs) are one family of proteins that modulate expression levels of genes in a space- and time-dependent manner. HATs and their molecular complexes are able to integrate multiple molecular inputs and mediate transcriptional levels by acetylating histone proteins. In mammals, 19 HATs have been described and are separated into five families (p300/CBP, MYST, GNAT, NCOA and transcription-related HATs). During embryogenesis, individual HATs are expressed or activated at specific times and locations to coordinate proper development. Not surprisingly, mutations in HATs lead to severe developmental abnormalities in the nervous system and increased neurodegeneration. This review focuses on our current understanding of HATs and their biological roles during neural development.
    Full-text · Article · May 2014 · Cell and Tissue Research
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    • "Given that typical human exomes carry between zero and five high confidence de novo coding variants [9,13,14,33-39] and the inclusive approach to generating the primary gene list (over 1,000 genes included in each case), the identification of a previously unreported de novo missense variant in the KMT2A gene in a single case is not by itself a significant finding. However, combined with the phenotypic overlap between individuals with de novo variants in KMT2A with WSS and these two unrelated patients, these findings strongly implicate a causal relationship between the observed variants and the clinical presentation of these individuals. "
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    ABSTRACT: Background Wiedemann-Steiner Syndrome (WSS) is characterized by short stature, a variety of dysmorphic facial and skeletal features, characteristic hypertrichosis cubiti (excessive hair on the elbows), mild-to-moderate developmental delay and intellectual disability. [MIM#: 605130]. Here we report two unrelated children for whom clinical exome sequencing of parent-proband trios was performed at UCLA, resulting in a molecular diagnosis of WSS and atypical clinical presentation. Case presentation For patient 1, clinical features at 9 years of age included developmental delay, craniofacial abnormalities, and multiple minor anomalies. Patient 2 presented at 1 year of age with developmental delay, microphthalmia, partial 3–4 left hand syndactyly, and craniofacial abnormalities. A de novo missense c.4342T>C variant and a de novo splice site c.4086+G>A variant were identified in the KMT2A gene in patients 1 and 2, respectively. Conclusions Based on the clinical and molecular findings, both patients appear to have novel presentations of WSS. As the hallmark hypertrichosis cubiti was not initially appreciated in either case, this syndrome was not suspected during the clinical evaluation. This report expands the phenotypic spectrum of the clinical phenotypes and KMT2A variants associated with WSS.
    Full-text · Article · May 2014 · BMC Medical Genetics
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