Genetic analysis of consanguineous families presenting with congenital ocular defects

- We enrolled eight consanguineous families affected with anophthalmia/microphthalmia from Pakistan and India.
- We performed Sanger sequencing of SOX2, ALDH1A3, OTX2, VSX2, RAX and FOXE3 in enrolled families.
- Sanger sequencing identified two novel mutations in ALDH1A3 and one novel mutation in FOXE3, solving three families.
- Sanger sequencing also identified a recurrent mutation in FOXE3 gene in two families.
- Whole exome sequencing was performed in two families, but the underlying causative mutation wasn't identified.

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.