ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
36 citing papers in PubMed, 63 citations in OpenAlex.
- Hereditary Congenital Cataract With Spastic Paraplegia Associated With a Missense PAX6 Variant (p.Arg26Trp).Cureus · 2026Article
- Epigenetic, Genetic, and Functional Germline Alterations ofCurrent issues in molecular biology · 2026Review
- A structure-guided approach to noncoding variant evaluation for transcription factor binding using AlphaFold 3.Nucleic acids research · 2026Article
- Next-Generation Sequencing in Congenital Eye Malformations: Identification of Genetic Causes and Comparison of Different Panel-Based Diagnostic Strategies.International journal of molecular sciences · 2025Article
- Comprehensive Analysis of Congenital Aniridia and Differential Diagnoses: Genetic Insights and Clinical Manifestations.Ophthalmology and therapy · 2025Review
- Strabismus in Genetic Syndromes: A Review.Clinical & experimental ophthalmology · 2025Review
- Complementary Roles of Structure and Variant Effect Predictors in RyR1 Clinical Interpretation.Human mutation · 2025Article
- Expression status transition ofF1000Research · 2025Article
- Understanding the heterogeneous performance of variant effect predictors across human protein-coding genes.Scientific reports · 2024Article
- Using computational approaches to enhance the interpretation of missense variants in the PAX6 gene.European journal of human genetics : EJHG · 2024Article
- The Systemic Genotype-Phenotype Characterization of PAX6-Related Eye Disease in 164 Chinese Families.Investigative ophthalmology & visual science · 2024Article
- Article
- Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants.Molecular systems biology · 2024Article
- Disruption of common ocular developmental pathways in patient-derived optic vesicle models of microphthalmia.Stem cell reports · 2024Article
- An Unusual Presentation of Novel Missense Variant inCurrent issues in molecular biology · 2023Article
- Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma.The British journal of ophthalmology · 2023Article
- A novel missense variant expands the phenotype and genotype of PAX6-associated foveal hypoplasia accompanied by various manifestations of anterior segment dysgenesis.BMC ophthalmology · 2023Article
- A novel PAX6 variant as the cause of aniridia in a Chinese patient with SRRRD.BMC medical genomics · 2023Article
- Correspondence between functional scores from deep mutational scans and predicted effects on protein stability.Protein science : a publication of the Protein Society · 2023Article
- Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene.European journal of human genetics : EJHG · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
31 authors at 20 institutions in 6 countries.
Funding
Abstract
purposeMost classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions.
methodsWe screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGU
resultsEight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease.
conclusionAltering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.