Axenfeld-Rieger syndrome associated with a megabase-scale inversion separating from 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 the or loci, yet many cases still remain undiagnosed. Here we used whole-genome sequencing to identify two non-coding structural variants associated with a typical presentation of -associated ARS: one with a 450 kb deletion removing a series of conserved enhancer elements distal to , and the second with a 12.5 Mb inversion displacing the gene from these same enhancer elements. Neither variant disrupted the gene itself, and therefore both were expected to reduce expression 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.