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Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.
Pubmed ID: 28513611
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Data analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.
View all literature mentionsAutomated system for constructing putative homology groups from complete gene sets of wide range of eukaryotic species. Databse that provides system for automatic detection of homologs, including paralogs and orthologs, among annotated genes of sequenced eukaryotic genomes. HomoloGene processing uses proteins from input organisms to compare and sequence homologs, mapping back to corresponding DNA sequences. Reports include homology and phenotype information drawn from Online Mendelian Inheritance in Man, Mouse Genome Informatics, Zebrafish Information Network, Saccharomyces Genome Database and FlyBase.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on January 9, 2023. An aggregated data platform for genome sequencing data created by a coalition of investigators seeking to aggregate and harmonize exome sequencing data from a variety of large-scale sequencing projects, and to make summary data available for the wider scientific community. The data set provided on this website spans 61,486 unrelated individuals sequenced as part of various disease-specific and population genetic studies. They have removed individuals affected by severe pediatric disease, so this data set should serve as a useful reference set of allele frequencies for severe disease studies. All of the raw data from these projects have been reprocessed through the same pipeline, and jointly variant-called to increase consistency across projects. They ask that you not publish global (genome-wide) analyses of these data until after the ExAC flagship paper has been published, estimated to be in early 2015. If you''re uncertain which category your analyses fall into, please email them. The aggregation and release of summary data from the exomes collected by the Exome Aggregation Consortium has been approved by the Partners IRB (protocol 2013P001477, Genomic approaches to gene discovery in rare neuromuscular diseases).
View all literature mentionsArchive of aggregated information about sequence variation and its relationship to human health. Provides reports of relationships among human variations and phenotypes along with supporting evidence. Submissions from clinical testing labs, research labs, locus-specific databases, expert panels and professional societies are welcome. Collects reports of variants found in patient samples, assertions made regarding their clinical significance, information about submitter, and other supporting data. Alleles described in submissions are mapped to reference sequences, and reported according to HGVS standard.
View all literature mentionsThe goal of the project is to discover novel genes and mechanisms contributing to heart, lung and blood disorders by pioneering the application of next-generation sequencing of the protein coding regions of the human genome across diverse, richly-phenotyped populations and to share these datasets and findings with the scientific community to extend and enrich the diagnosis, management and treatment of heart, lung and blood disorders. The groups participating and collaborating in the NHLBI GO ESP include: Seattle GO - University of Washington, Seattle, WA Broad GO - Broad Institute of MIT and Harvard, Cambridge, MA WHISP GO - Ohio State University Medical Center, Columbus, OH Lung GO - University of Washington, Seattle, WA WashU GO - Washington University, St. Louis, MO Heart GO - University of Virginia Health System, Charlottesville, VA ChargeS GO - University of Texas Health Sciences Center at Houston
View all literature mentionsSoftware tool which predicts possible impact of amino acid substitution on structure and function of human protein using straightforward physical and comparative considerations. PolyPhen-2 is new development of PolyPhen tool for annotating coding nonsynonymous SNPs.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on September 23,2022. Software for DNA sequencing analysis that integates with Sanger Sequencing files generated by Applied Biosystems Genetic Analyzers, MegaBACE, and Beckman CEQ electrophoresis systems. It can be used to find single nucleotide polymorphisms (SNPs), insertions and deletions (INDELS), and somatic mutations in direct sequencing, PCR sequencing, mitochondrial DNA sequencing, and resequencing projects.
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