An individual with blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B

Abstract

Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) is an autosomal dominant disorder caused by mutations in FOXL2. We identified an individual with BPES and additional phenotypic features who did not have a FOXL2 mutation. We used whole exome sequencing to identify a de novo mutation in KAT6B (lysine acetyltransferase 6B) in this individual. The mutation was a 2 bp insertion leading to a frameshift which resulted in a premature stop codon. The resulting truncated protein does not have the C-terminal serine/methionine transcription activation domain necessary for interaction with other transcriptional and epigenetic regulators. This mutation likely has a dominant-negative or gain-of-function effect, similar to those observed in other genetic disorders resulting from KAT6B mutations, including Say-Barber-Biesecker-Young-Simpson (SBBYSS) and Genitopatellar syndrome (GTPTS). Thus, our subject’s phenotype broadens the spectrum of clinical findings associated with mutations in KAT6B. Furthermore, our results suggest that individuals with BPES without a FOXL2 mutation should be tested for KAT6B mutations. The transcriptional and epigenetic regulation mediated by KAT6B appears crucial to early developmental processes, which when perturbed can lead to a wide spectrum of phenotypic outcomes.

Deficiency of the Chromatin Regulator Brpf1 Causes Abnormal Brain Development

“…Mice with residual Morf expression display abnormalities in the neocortex (27). Importantly, mutations in the MORF gene causes Noonan syndrome-like disorder (21), Ohdo syndrome (22), genitopatellar syndrome (23,24), and blepharophimosis-ptosis-epicanthus inversus syndrome (25). Patients with these diseases display intellectual disability and ill-formed corpus callosum (26).…”

“…Psychiatric illness is a late-occurring feature of this syndrome, and some patients are predisposed to schizophrenia. The MORF gene is mutated in four neurodevelopmental disorders as follows: Noonan syndrome-like disorder (21); Ohdo syndrome (22); genitopatellar syndrome (23,24); and blepharophimosis-ptosis-epicanthus inversus syndrome (25). Intellectual disability is common to these disorders, and the patients often display callosal aplasia or hypoplasia (26).…”

De novo KAT6B Mutation Identified with Whole-Exome Sequencing in a Girl with Say-Barber/Biesecker/Young-Simpson Syndrome

“…Additional features expanding the phenotype associated with mutations in KAT6B were described in an individual with blephrophimosis-ptosis-epicanthus inversus syndrome who had cryptorchidism, right hydrocele, wide-spaced nipples, and slight syndactyly of toes 2 and 3 [Yu et al, 2014]. Thyroid function was normal.…”

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

“…Notably, MOZ has also been shown to play important roles in cardiac septum development (78). Dominant mutations in MORF are associated with Noonan syndrome, Say-Barber-Biesecker-YoungSimpson syndrome, genitopatellar syndrome, and blepharophimosis-ptosis-epicanthus inversus syndrome (7)(8)(9)(10)(11)(12). The common phenotypes shared between at least two of these four syndromes include abnormal facial features, intellectual disability, congenital heart defects, and genital anomalies.…”

“…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.…”