Genetic analysis of consanguineous families presenting with congenital ocular defects.

Anophthalmia and microphthalmia (A/M) are a group of rare developmental disorders that affect the size of the ocular globe. A/M may present as the sole clinical feature, but are also frequently found in a variety of syndromes. A/M is genetically heterogeneous and can be caused by chromosomal aberrations, copy number variations and single gene mutations. To date, A/M has been caused by mutations in at least 20 genes that show different modes of inheritance. In this study, we enrolled eight consanguineous families with A/M, including seven from Pakistan and one from India. Sanger and exome sequencing of DNA samples from these families identified three novel mutations including two mutations in the Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3) gene, [c.1310_1311delAT; p.(Tyr437Trpfs*44) and c.964G > A; p.(Val322Met)] and a single missense mutation in Forkhead Box E3 (FOXE3) gene, [c.289A > G p.(Ile97Val)]. Additionally two previously reported mutations were identified in FOXE3 and in Visual System Homeobox 2 (VSX2). This is the first comprehensive study on families with A/M from the Indian subcontinent which provides further evidence for the involvement of known genes with novel and recurrent mutations.

Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis.

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.