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.

Keywords: BPES; KAT6B; blepharophimosis; epicanthus inversus; ptosis; whole exome sequencing.

FIG 1

Clinical features of the subject. A–D: subject at 2 months of age; note blepharophimosis, ptosis, epicanthus inversus (A), posteriorly angulated ears with thickened superior helix and prominent antihelix (B), and slight 2–3 syndactyly of toes in addition to overlapping toes (C, D). E,F: subject at 3.5 years of age following oculoplastic surgery to correct ptosis; note right-sided preauricular ear pit (F, indicated by arrow). G–I: subject at 12 years of age; note the recurrence of ptosis (L>R), arched eyebrows, abnormal ears, thin upper lip vermilion, small pointed chin, downsloping shoulders and wide-spaced and low-set nipples.

FIG. 2

Pathogenic mutations in KAT6B. A: Chromatograph showing Sanger sequencing results of the subject shows a rare de novo heterozygous c.5623_5624dupCA (p.Gln1875Hisfs*5) frameshift mutation while parents have two normal alleles. The 2 bp CA duplication in the subject results in mixed peaks after the duplication site. B: In the top panel, protein domains of KAT6B are shown. It has a histone binding domain consisting of H15 (linker histones H1- and H5-like module) and PHD (plant homeodomain zink fingers) domains, a histone acetylation HAT (histone acetyltransferase) domain, an acidic glutamate/aspartate-rich domain, and a transcription activation serine/methionine-rich domain [Champagne et al., 1999; Pelletier et al., 2002]. The second panel shows KAT6B coding exons as gray boxes with exon number indicated. Locations of pathogenic mutations identified in our subject and other recently identified genetic disorders are indicated by arrows. Mutations found in our subject (red), SBBYSS (brown and orange), and GTPTS (green and blue) are always nonsense or frameshift truncating mutations.