EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders

Lenassi, Eva; Carvalho, Ana Carolina de; Thormann, Anja; Fletcher, Tracy; Hardcastle, Claire; Hunt, Sarah; Sergouniotis, Panagiotis I.; Michaelides, Michel; Webster, Andrew R.; Cunningham, Fiona; Ramsden, Simon; FitzPatrick, David R.; Black, Graeme; Ellingford, Jamie M

doi:10.1101/2021.07.23.21261017

Cited by 2 publications

(1 citation statement)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Putatively active UCNEs associated with genes expressed in retina were filtered further based on their implication in disease as retrieved from the comprehensive gene-disease pairs and attributes list provided by G2P (Eye and Developmental Disease -DD-Panels; 2022-03-17) (Lenassi et al, 2021;Thormann et al, 2019) extended with the NCMD-associated IRX1 locus (Small et al, 2016). To assess the contribution of genomic variation within these loci to disease, an analysis was performed to detect small variants (SNVs, and indels < 50bp), and large structural variants (SVs) including copy number variants (CNVs) overlapping these disease-gene associated UCNE loci through query of a sub-cohort of participants with rare eye disease phenotypes (n = 3,220) from the 100,000 Genomes Project (100KGP, Genomics England).…”

Section: Interrogation Of Wgs Data In a Rare Eye Disease Cohortmentioning

confidence: 99%

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

Soriano

Rey

Mukherjee

et al. 2023

Preprint

View full text Add to dashboard Cite

Cross-species genome comparisons have revealed a substantial number of ultraconserved non-coding elements (UCNEs). Several of these elements have proved to be essential tissue- and cell type-specificcis-regulators of developmental gene expression. Here, we characterized a set of UCNEs, as candidate CREs (cCREs) during retinal development and evaluate the contribution of their genomic variation to rare eye diseases, for which pathogenic non-coding variants are emerging. Integration of bulk and single-cell retinal multi-omics data revealed 594 genes under potentialcis-regulatory control of UCNEs, of which 45 are implicated in rare eye disease. Mining of candidatecis-regulatory UCNEs in WGS data derived from the rare eye disease cohort of Genomics England revealed 178 ultrarare variants within 84 UCNEs associated with 29 disease genes. Overall, we provide a comprehensive annotation of ultraconserved non-coding regions acting as cCREs during retinal development which can be targets of non-coding variation underlying rare eye diseases.

show abstract

Section: Interrogation Of Wgs Data In a Rare Eye Disease Cohortmentioning

confidence: 99%

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

Soriano

Rey

Mukherjee

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

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

Hall,

Parry,

Halachev

et al. 2023

J Med Genet

Self Cite

View full text Add to dashboard Cite

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 thePAX6locus.MethodsShort-read whole genome sequencing was performed on 51 (39 affected) individuals from 37 different families who had screened negative for mutations in thePAX6coding 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 thePAX6locus. Of these 19 families, 1 has a novel heterozygousPAX6frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites ofPAX65′ 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 ofPAX6, 3 have deletions encompassing criticalPAX6 cis-regulatory elements, 2 have balanced inversions with disruptive breakpoints within thePAX6locus and 2 have complex rearrangements disruptingPAX6. The remaining 3 of 22 families have deletions encompassingFOXC1(a known cause of atypical aniridia). Seven of the causative variants occurredde novoand one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified inPAX6 cis-regulatory elements.ConclusionWhole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.

show abstract

EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders

Cited by 2 publications

References 37 publications

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

Multi-omics analysis in human retina uncovers ultraconservedcis-regulatory elements at rare eye disease loci

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

Contact Info

Product

Resources

About