Syndromic manifestations in aniridia patients with PAX6 point mutations

The PAX6 gene is associated with various congenital ocular defects.Aniridia is typically associated with mutations introducing a premature STOP codon, whereas missense mutations, of which the majority are located in the paired domain, lead to variant phenotypes. The study provides a survey of PAX6 mutations in patients presenting with extraocular features. We performed sequencing of PAX6 exons and boundaries, search for intragenic rearrangements (QMPSF/qPCR) and CNV analysis (aCGH) in 127 index cases. Genotype-phenotype correlations were searched.We identified mutations in 90% of patients. Yet, a high inter- and intra-familial clinical variability, we noted that heterozygous missense mutations (Asn64, Gly65, Cys66) in Paired-Domain medial 3rd helix were associated with severe phenotypes (e.g. anophthalmia, and CNS malformations). Cases bearing compound heterozygous mutations were affected with severe malformations. Consistent with previous studies, mutations introducing a premature stop codon and gene rearrangements made up the majority. Some genotype-phenotype correlations could be drawn. It is necessary to better delineate the expression of PAX6 mutations to provide patients with a prognosis and to set up a tailor-made follow-up.