FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3

Metsu, Sofie; Rooms, Liesbeth; Rainger, Jacqueline K.; Taylor, Martin S.; Bengani, Hemant; Wilson, David I.; Chilamakuri, Chandra Sekhar Reddy; Morrison, Harris; Vandeweyer, Geert; Reyniers, Edwin; Douglas, Evelyn; Thompson, Greg; Haan, Eric; Gécz, Jozef; FitzPatrick, David R.; Kooy, R. Frank

doi:10.1371/journal.pgen.1004242

Cited by 45 publications

(64 citation statements)

References 54 publications

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“…2D). This is consistent with the local transcriptional repression associated with FRAXA [Oberle et al, 1991] and other reported FSFS Winnepenninckx et al, 2007;Metsu et al, 2014].…”

supporting

confidence: 92%

A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

et al. 2014

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We report de novo occurrence of the 7p11.2 folate-sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG-repeat expansion mutation (∼450 repeats) in a 5' intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband-derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG-repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed.

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“…2D). This is consistent with the local transcriptional repression associated with FRAXA [Oberle et al, 1991] and other reported FSFS Winnepenninckx et al, 2007;Metsu et al, 2014].…”

supporting

confidence: 92%

A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

et al. 2014

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“…1986) as well as in patients with schizophrenia (Chen et al 1998). It was not until recent that this fragile site was molecularly characterized as a site with CGG repeat expansion impacting the AFF3 gene and was detected in families with a broad range of neurodevelopmental disorders (Metsu et al 2014a). …”

Section: 2 Early History Of Chromosome Fragile Site Discoveries Rementioning

confidence: 99%

Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

Feng

Chakraborty

2017

Advances in Experimental Medicine and Biology

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Chromosome fragile sites are a fascinating cytogenetic phenomenon now widely implicated in a slew of human diseases ranging from neurological disorders to cancer. Yet, the paths leading to these revelations were far from direct, and the number of fragile sites that have been molecularly cloned with known disease-associated genes remains modest. Moreover, as more fragile sites were being discovered, research interests in some of the earliest discovered fragile sites ebbed away, leaving a number of unsolved mysteries in chromosome biology. In this review we attempt to recount some of the early discoveries of fragile sites and highlight those phenomena that have eluded intense scrutiny but remain extremely relevant in our understanding of the mechanisms of chromosome fragility. We then survey the literature for disease association for a comprehensive list of fragile sites. We also review recent studies addressing the underlying cause of chromosome fragility while highlighting some ongoing debates. We report an observed enrichment for R-loop forming sequences in fragile site-associated genes than genomic average. Finally, we will leave the reader with some lingering questions to provoke discussion and inspire further scientific inquiries.

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“…Metsu22 recently mapped a folate-sensitive fragile site (FSFS) 80 kb upstream of AFF3 , located in a brain-active alternative promoter of AFF3 . FSFS are points on the chromosomes that tend to form gaps and break under stressful conditions in the presence of folate.…”

Section: Resultsmentioning

confidence: 99%

A sequence variant associating with educational attainment also affects childhood cognition

Gunnarsson

Jónsdóttir

Björnsdóttir

et al. 2016

Sci Rep

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Only a few common variants in the sequence of the genome have been shown to impact cognitive traits. Here we demonstrate that polygenic scores of educational attainment predict specific aspects of childhood cognition, as measured with IQ. Recently, three sequence variants were shown to associate with educational attainment, a confluence phenotype of genetic and environmental factors contributing to academic success. We show that one of these variants associating with educational attainment, rs4851266-T, also associates with Verbal IQ in dyslexic children (P = 4.3 × 10−4, β = 0.16 s.d.). The effect of 0.16 s.d. corresponds to 1.4 IQ points for heterozygotes and 2.8 IQ points for homozygotes. We verified this association in independent samples consisting of adults (P = 8.3 × 10−5, β = 0.12 s.d., combined P = 2.2 x 10−7, β = 0.14 s.d.). Childhood cognition is unlikely to be affected by education attained later in life, and the variant explains a greater fraction of the variance in verbal IQ than in educational attainment (0.7% vs 0.12%,. P = 1.0 × 10−5).

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FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3

Cited by 45 publications

References 54 publications

A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

A sequence variant associating with educational attainment also affects childhood cognition

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