Axenfeld-Rieger syndrome associated with a megabase-scale inversion separatingPITX2from a conserved enhancer locus

Axenfeld–Rieger Syndrome (ARS) is an autosomal dominant condition with both ocular and non-ocular manifestations. ARS is primarily caused by coding variants at thePITX2orFOXC1loci, yet many cases still remain undiagnosed. Here we used whole-genome sequencing to identify two non-coding structural variants associated with a typical presentation ofPITX2-associated ARS: one with a 450 kb deletion removing a series of conserved enhancer elements distal toPITX2, and the second with a 12.5 Mb inversion displacing thePITX2gene from these same enhancer elements. Neither variant disrupted thePITX2gene itself, and therefore both were expected to reducePITX2expression by disrupting its proximity or access to enhancer elements. Enhancer-disrupting intergenic inversions therefore represent a unique genetic mechanism for the development of ARS, which should be carefully considered in the context of ARS and other conditions without a conclusive genetic diagnosis.