Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features

Abstract

Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: NM_001099412.1: c.3116_3117 delCT, p.(Ser1039∗); c.3830_3831insTT, p.(Arg1278Serfs∗17); c.3879 dupA, p.(Glu1294Argfs∗19); c.4108G>T p.(Glu1370∗) and c.4292 dupT, p.(Leu1431Phefs∗8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects.

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

“…Related to the cerebral defects, Morf is important for regulating neural stem cells [72,73]. These findings shed some light on defects characteristic of developmental disorders due to mutations in the MOZ and MORF genes [74][75][76][77][78][79]. The phenotypes observed with these mutant mice indicate that although they are interchangeable in various molecular and cell-based studies in vitro [26,34,36], MOZ and MORF have quite distinct functions in vivo.…”

“…3A) [36]. The bromodomain of BRPF1 has acetyllysine-binding ability [57], whereas the PZP modules of BRPF1 and BRPF2 recognize the unmodified N-terminus of histone H3 [46,58] and the second PHD finger of BRPF2 is also known to bind directly [78,79,130,134]. Abbreviations: CBP, CREB-binding protein; p300, E1A-associated p300 kDa protein (paralogous to CBP); TIF2, transcription intermediary factor 2 (known to bind p300 and CBP).…”

Clinical application of whole-exome sequencing across clinical indications

“…Utilizing the power of our large data set, we were able to identify novel candidate genes in which multiple patients with similar phenotypes had rare variants predicted to result in loss of function, many of which were de novo. Access to this large number of cases has proven extremely valu- [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] As a result of our experience, we believe that candidate genes should be reported from WES analysis and shared in databases, such as GeneMatcher, so that clinicians, researchers, and clinical laboratories can be connected to facilitate more rapid dissemination of information and validation of novel disease genes. Our series is larger than previously reported clinical diagnostic series and has the power to begin to address the yield of WES for a large number of clinical indications.…”

Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

“…Heterozygous mutations in MOZ have been identified in patients with microcephaly and global developmental delay, including intellectual disability and cardiac defects (5,6). Notably, MOZ has also been shown to play important roles in cardiac septum development (78).…”

“…Lysine acetyltransferase 6 (KAT6) belongs to the MYST family and has been linked to cell cycle regulation and leukemia (2)(3)(4). In addition, mutations and misregulation of the human KAT6 genes, MOZ/MORF, have been identified in solid tumors and patients with developmental disorders (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). To gain better understanding of the roles of KAT6 HATs in human diseases, it is critical to know how their functions are regulated.…”