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Exome sequencing reveals novel homozygous FOXE3 mutation in microphthalmos with staphylomatous malformation

Microphthalmia is a structural birth defect in which one or both eyes are abnormally small. Microphthalmia may be classified as simple in which the eye is anatomically normal except for the decreased axial length or complex in which the eye is associated with anterior and/or posterior segment dysgenesis. FOXE3 gene at chromosome 1p32 is a forkhead transcription factor expressed in the lens of the eye. FOXE3 is critical for proliferation and differentiation of the lens epithelium and plays an important role in anterior segment morphogenesis and differentiation. Heterozygous mutations in this gene inherited in an autosomal dominant pattern result in a spectrum of ocular diseases that include posterior embryotoxon, Peters’ anomaly, congenital cataracts, and iris colobomas. Recessive mutations in this gene result in a rare, severe form of ocular dysgenesis that includes microphthalmos, aphakia, and sclerocornea. We performed exome sequencing in a consanguineous family from India with severe bilateral ocular dysgenesis and unilateral staphylomatous malformation and report a novel homozygous mutation in FOXE3 shared by the affected family members. Our report adds to the phenotypic and mutational spectrum of autosomal recessive microphthalmos caused by the FOXE3 gene. Subjects from a consanguineous family (Figure 1A)with bilateral ocular dysgenesis were recruited and examined after informed consent. The study was approved by the Institutional Review Board of the Srikiran Institute of Ophthalmology and followed the tenets of the Declaration of Helsinki. All the three affected individuals presented with complex microphthalmos, bilateral aphakia, and unilateral anterior staphyloma (Table 1 and Figure 2). No systemic abnormalities were found on general physical examination of the three affected family members. The CYP1B1 gene was screened by Sanger sequencing using genomic DNA from the affected subjects: SIO44, SIO47, and SIO52 with primers selected using ExonPrimer and Primer3 (Helmholtz Center Munich, Institute of Human Genetics). Sanger sequencing did not reveal any coding sequence mutations in CYP1B1. Whole exome capture was performed on five subjects (SIO44, SIO45, SIO47, SIO48, and SIO52) using the Agilent SureSelect Human All Exon 44Mb v2.0 bait set (Agilent Technologies, USA) and the sequencing