PMC4414115_01
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.
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F1
In addition to blepharophimosis, ptosis and epicanthus inversus normally associated with BPES, he had cryptorchidism, right hydrocele, wide-spaced nipples, and slight 2-3 syndactyly of toes (Fig. 1).
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. 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.
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F2
The mutation in the subject was verified by Sanger sequencing (Fig. 2A). KAT6B, and resulted in frameshift and a premature stop codon, p.Gln1875Hisfs*5, interrupting the C-terminal of KAT6B which has a serine/methionine-rich transcription activation domain (Fig. 2B). KAT6B is a histone acetyltransferase believed to be an epigenetic and transcriptional regulator for a broad range of cellular processes.