Molecular characterization of Axenfeld-Rieger spectrum and other anterior segment dysgeneses in a sample of Mexican patients.

Background: Anterior segment dysgenesis (ASD) and Axenfeld-Rieger spectrum (ARS) are mainly due to PITX2 and FOXC1 defects, but it is difficult in some patients to differentiate among PITX2-, FOXC1-, PAX6- and CYP1B1-related disorders. Here, we set out to characterize the pathogenic variants (PV) in PITX2, FOXC1, CYP1B1 and PAX6 in nine unrelated Mexican ARS/ASD patients and in their available affected/unaffected relatives.

Materials And Methods: Automated Sanger sequencing of PITX2, FOXC1, PAX6 and CYP1B1 was performed; those patients without a PV were subsequently analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA) for PITX2, FOXC1 and PAX6. Missense variants were evaluated with the MutPred, Provean, PMUT, SIFT, PolyPhen-2, CUPSAT and HOPE programs.

Results: We identified three novel PV in PITX2 (NM_153427.2:c.217G>A, c.233T>C and c.279del) and two in FOXC1 [NM_001453.2:c.274C>T (novel) and c.454T>A] in five ARS patients. The previously reported FOXC1 c.367C>T or p.(Gln123*) variant was identified in a patient with ASD. The ocular phenotype related to FOXC1 included aniridia, corneal opacity and early onset glaucoma, while an asymmetric ocular phenotype and aniridia were associated with PITX2. No gene rearrangements were documented by MLPA analysis, nor were any PV identified in PAX6 or CYP1B1.

Conclusions: Heterozygous PV in the PITX2 and FOXC1 genes accounted for 66% (6/9) of the ARS/ASD cases. The absence of PAX6 or CYP1B1 abnormalities could reflect our small sample size, although their analysis could be justified in ARS/ASD patients that present with congenital glaucoma or aniridia.