FRA2A is a CGG repeat expansion associated with silencing of AFF3.
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.
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Sofie
S
Metsu
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Liesbeth
L
Rooms
Medical and Developmental Genetics Section, MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
Jacqueline
J
Rainger
Medical and Developmental Genetics Section, MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
Martin S
MS
Taylor
Medical and Developmental Genetics Section, MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
Hemant
H
Bengani
University of Southampton, Centre for Human Development, Stem Cells and Regeneration, Human Genetics, Southampton, United Kingdom.
David I
DI
Wilson
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Chandra Sekhar Reddy
CS
Chilamakuri
Medical and Developmental Genetics Section, MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
Harris
H
Morrison
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Geert
G
Vandeweyer
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Edwin
E
Reyniers
Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.
Evelyn
E
Douglas
Department of Paediatrics, The University of Adelaide, Adelaide, South Australia, Australia; Department of Paediatrics and Child Health, Flinders University, Adelaide, South Australia, Australia.
Geoffrey
G
Thompson
Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia; South Australian Clinical Genetic Service, SA Pathology (at Women's and Children's Hospital), Adelaide, South Australia, Australia.
Eric
E
Haan
Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia; Department of Paediatrics, The University of Adelaide, Adelaide, South Australia, Australia.
Jozef
J
Gecz
Medical and Developmental Genetics Section, MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
David R
DR
Fitzpatrick
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
R Frank
RF
Kooy
D000483:Alleles; D043283:Chromosome Fragile Sites / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D051921:Fos-Related Antigen-2 / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C097738:AFF3 protein, human; C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; D009687:Nuclear Proteins