Hall, Hildegard Nikki;
Parry, David;
Halachev, Mihail;
Williamson, Kathleen A;
Donnelly, Kevin;
Campos Parada, Jose;
Bhatia, Shipra;
... Meynert, Alison; + view all
(2023)
Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia.
Journal of Medical Genetics
, 61
(3)
pp. 250-261.
10.1136/jmg-2023-109181.
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Abstract
Background: Classic 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 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 out of 37 (59%) families. In 19 out of 22 families, the causative genomic changes have an interpretable deleterious impact on the PAX6 locus. Of these 19 families, 1 has a novel heterozygous PAX6 frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites of PAX6 5′ 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 PAX6 locus 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 novo and 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. Conclusion Whole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.
| Type: | Article |
|---|---|
| Title: | Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1136/jmg-2023-109181 |
| Publisher version: | http://dx.doi.org/10.1136/jmg-2023-109181 |
| Language: | English |
| Additional information: | This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, Eye Diseases, Genetic Testing, Mutation, STRUCTURAL VARIANTS, PAX6 GENE, MUTATION, PHENOTYPE, SPECTRUM, REVEALS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10189264 |
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