부산대학교 도서관

BackgroundClassic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and progressive opacification of the cornea. >90% of cases of classic aniridia are caused by heterozygous, loss-of-function variants affecting the PAX6locus.MethodsShort-read whole genome sequencing was performed on 51 (39 affected) individuals from 37 different families who had screened negative for mutations in the PAX6coding region.ResultsLikely causative mutations were identified in 22 out of 37 (59%) families. In 19 out of 22 families, the causative genomic changes have an interpretable deleterious impact on the PAX6locus. Of these 19 families, 1 has a novel heterozygous PAX6frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites of PAX65′ non-coding exons and 2 have deep intronic SNV (one novel) resulting in gain of a donor splice site. In 12 out of 19, the causative variants are large-scale structural variants; 5 have partial or whole gene deletions of PAX6, 3 have deletions encompassing critical PAX6 cis-regulatory elements, 2 have balanced inversions with disruptive breakpoints within the PAX6locus and 2 have complex rearrangements disrupting PAX6. The remaining 3 of 22 families have deletions encompassing FOXC1(a known cause of atypical aniridia). Seven of the causative variants occurred de novoand one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified in PAX6 cis-regulatory elements.ConclusionWhole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.