We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea,
microphthalmia,
hypotonia and developmental delays. Sanger sequencing verified two
Peroxidasin (
PXDN) mutations in both sibs--a maternally inherited,
nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature
protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional
PXDN mutations in a sporadic male with bilateral
microphthalmia,
cataracts and anterior segment dysgenesis--a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in
PXDN were previously reported in three families with congenital
cataracts, microcornea, sclerocornea and developmental
glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective
peroxidasin has been shown to impair
sulfilimine bond formation in
collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for
PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that
PXDN sequencing should be considered in
microphthalmia with anterior segment dysgenesis.