Axenfeld-Rieger syndrome associated with a megabase-scale inversion separating PITX2 from a conserved enhancer locus
Mitchell, L. A.; Schmidt, J.; Souzeau, E.; Knight, L. S. W.; Maxwell, G.; Dubowsky, A.; Lim, R.; Formaini, E.; Welland, M.; Simons, C.; MacArthur, D. G.; Wiggs, J. L.; Craig, J. E.; Siggs, O. M.
Show abstract
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 PITX2 or FOXC1 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 PITX2-associated ARS: one with a 450 kb deletion removing a series of conserved enhancer elements distal to PITX2, and the second with a 12.5 Mb inversion displacing the PITX2 gene from these same enhancer elements. Neither variant disrupted the PITX2 gene itself, and therefore both were expected to reduce PITX2 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.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders 96%
- A comparative medical genomics approach may facilitate the interpretation of rare missense variation 94%
- Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases 94%
Similar papers in this journal
- Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease 94%
- Genome Sequencing and Comprehensive Rare Variant Analysis of 465 Families with Neurodevelopmental Disorders 94%
- Genetic risk estimates for offspring of patients with Stargardt disease 93%
Similar papers in this journal
- Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome 93%
- Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting 93%
- Genome sequencing reveals the impact of non-canonical exon inclusions in rare genetic disease 93%
Similar papers in this journal
- Genetic Diagnosis of Facioscapulohumeral Muscular Dystrophy Type 1 Using Rare Variant Linkage Analysis and Long Read Genome Sequencing 94%
- Early Diagnosis of Vascular Ehlers-Danlos Syndrome Through AI-Powered Facial Analysis: Results from the Montalcino Aortic Consortium 91%
- Combined Bioinformatic and Splicing Analysis of Likely Benign Intronic and Synonymous Variants Reveals Evidence for Pathogenicity 90%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.