ArticlePLoS genetics2014
FRA2A is a CGG repeat expansion associated with silencing of AFF3.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 54 citations in OpenAlex.
- The Tale of the Guanosine Tract in Repeat Expansion Disorders.Molecular neurobiology · 2026Review
- A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- STRchive: a dynamic resource detailing population-level and locus-specific insights at tandem repeat disease loci.Genome medicine · 2025Article
- Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.Molecular neurodegeneration · 2024Article
- A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability.Nature genetics · 2024Article
- Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.Genome medicine · 2024Article
- Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.medRxiv : the preprint server for health sciences · 2024Article
- Unravelling the link between neurodevelopmental disorders and short tandem CGG-repeat expansions.Emerging topics in life sciences · 2023Review
- Gene-Environment Interactions in Repeat Expansion Diseases: Mechanisms of Environmentally Induced Repeat Instability.Biomedicines · 2023Review
- Review
- Advancing genomic technologies and clinical awareness accelerates discovery of disease-associated tandem repeat sequences.Genome research · 2022Review
- Fragile sites, chromosomal lesions, tandem repeats, and disease.Frontiers in genetics · 2022Review
- Transcription Pause and Escape in Neurodevelopmental Disorders.Frontiers in neuroscience · 2022Review
- GC-rich repeat expansions: associated disorders and mechanisms.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2021Article
- Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.American journal of human genetics · 2021Article
- Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease.Scientific reports · 2021Article
- Common Threads: Aphidicolin-Inducible and Folate-Sensitive Fragile Sites in the Human Genome.Frontiers in genetics · 2021Review
- Language Impairment with a Partial Duplication ofMolecular syndromology · 2020Article
- The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters.Scientific reports · 2020Article
- A Survey of Rare Epigenetic Variation in 23,116 Human Genomes Identifies Disease-Relevant Epivariations and CGG Expansions.American journal of human genetics · 2020Article
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Authors and funding
16 authors at 7 institutions in 4 countries.
Funding
Abstract
Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship.
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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.