Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia

Nikki Hall, David A. Parry, Mihail Halachev, Kathy Williamson, Kevin Donnelly, Jose Campos Parada, Shipra Bhatia, Jeffrey Joseph, Simon Holden, Trine E Prescott, Pierre Bitoun, Edwin Kirk, Ruth Newbury-Ecob, Katherine Lachlan, Juan Bernar, Veronica Van Heyningen, David R FitzPatrick, Alison M Meynert*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background: Classical aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and an adult-onset progressive opacification of the cornea¬¬. >90% of classical aniridia is caused by heterozygous, loss of function variants affecting the PAX6 locus. Methods: Short-read whole genome sequencing was performed on 51 (39 affected) individuals from 37 different families who had screened negative for mutations in the PAX6 coding region. Results: Likely causative mutations were identified in 22/37 (59%) families. In 19/22 families the causative genomic changes have an interpretable deleterious impact on the PAX6 locus. 1/19 has a novel heterozygous PAX6 frameshift variant missed on previous screens. 4/19 ¬have single nucleotide variants (one novel) affecting essential splice sites of PAX6 5’ non-coding exons. 2/19 have deep intronic SNV (one novel) resulting in gain of a donor splice site. In 12/19 the causative variants are large-scale structural variants (SV); 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 PAX6 locus and 2 have complex rearrangements disrupting PAX6. The remaining 3/22 families have deletions encompassing FOXC1 (a known cause of atypical aniridia). Seven of the causative variants occurred de novo and one co-segregated with familial aniridia. We were unable to establish inheritance status in remaining probands. No plausibly causative SNVs were identified in PAX6 cis-regulatory elements. Conclusion: Whole genome sequencing proves an effective diagnostic test in most individuals with previously-unexplained aniridia
Original languageEnglish
JournalJournal of Medical Genetics
Publication statusPublished - 30 Nov 2023


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