scholarly journals DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome

2020 ◽  
Vol 21 (20) ◽  
pp. 7735
Author(s):  
Claudine M Kraan ◽  
Emma K Baker ◽  
Marta Arpone ◽  
Minh Bui ◽  
Ling Ling ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Single Gene ◽  
Intellectual Functioning ◽  
Dried Blood Spots ◽  
Reference Ranges ◽  
Mrna Levels ◽  
Blood Spots ◽  
Fmr1 Mrna

Fragile X syndrome (FXS) is a leading single-gene cause of intellectual disability (ID) with autism features. This study analysed diagnostic and prognostic utility of the Fragile X-Related Epigenetic Element 2 DNA methylation (FREE2m) assessed by Methylation Specific-Quantitative Melt Analysis and the EpiTYPER system, in retrospectively retrieved newborn blood spots (NBS) and newly created dried blood spots (DBS) from 65 children with FXS (~2–17 years). A further 168 NBS from infants from the general population were used to establish control reference ranges, in both sexes. FREE2m analysis showed sensitivity and specificity approaching 100%. In FXS males, NBS FREE2m strongly correlated with intellectual functioning and autism features, however associations were not as strong for FXS females. Fragile X mental retardation 1 gene (FMR1) mRNA levels in blood were correlated with FREE2m in both NBS and DBS, for both sexes. In females, DNAm was significantly increased at birth with a decrease in childhood. The findings support the use of FREE2m analysis in newborns for screening, diagnostic and prognostic testing in FXS.

scholarly journals Small Molecules Targeting H3K9 Methylation Prevent Silencing of Reactivated FMR1 Alleles in Fragile X Syndrome Patient Derived Cells

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 356 ◽  
Author(s):  
Daman Kumari ◽  
Nicholas Sciascia ◽  
Karen Usdin
Keyword(s):  
Dna Methylation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Mrna Levels ◽  
H3k9 Methylation ◽  
Methyl Transferase ◽  
Cgg Repeat ◽  
Heterochromatin Formation ◽  
Gene Reactivation

In fragile X syndrome (FXS), expansion of a CGG repeat tract in the 5′-untranslated region of the FMR1 gene to >200 repeats causes transcriptional silencing by inducing heterochromatin formation. Understanding the mechanism of FMR1 silencing is important as gene reactivation is a potential treatment approach for FXS. To date, only the DNA demethylating drug 5-azadeoxycytidine (AZA) has proved effective at gene reactivation; however, this drug is toxic. The repressive H3K9 methylation mark is enriched on the FMR1 gene in FXS patient cells and is thus a potential druggable target. However, its contribution to the silencing process is unclear. Here, we studied the effect of small molecule inhibitors of H3K9 methylation on FMR1 expression in FXS patient cells. Chaetocin showed a small effect on FMR1 gene reactivation and a synergistic effect on FMR1 mRNA levels when used in combination with AZA. Additionally, chaetocin, BIX01294 and 3-Deazaneplanocin A (DZNep) were able to significantly delay the re-silencing of AZA-reactivated FMR1 alleles. These data are consistent with the idea that H3K9 methylation precedes DNA methylation and that removal of DNA methylation is necessary to see the optimal effect of histone methyl-transferase (HMT) inhibitors on FMR1 gene expression. Nonetheless, our data also show that drugs targeting repressive H3K9 methylation marks are able to produce sustained reactivation of the FMR1 gene after a single dose of AZA.

scholarly journals Autism Profiles of Males With Fragile X Syndrome

2008 ◽  
Vol 113 (6) ◽  
pp. 427-438 ◽  
Author(s):  
Susan W. Harris ◽  
David Hessl ◽  
Beth Goodlin-Jones ◽  
Jessica Ferranti ◽  
Susan Bacalman ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Diagnosis ◽  
Cgg Repeat ◽  
Molecular Features ◽  
Fmr1 Mrna ◽  
Two Measures ◽  
Dsm Iv ◽  
Relationship Of ◽  
The Relationship

Abstract Autism, which is common in individuals with fragile X syndrome, is often difficult to diagnose. We compared the diagnostic classifications of two measures for autism diagnosis, the ADOS and the ADI-R, in addition to the DSM-IV-TR in 63 males with this syndrome. Overall, 30% of the subjects met criteria for autistic disorder and 30% met criteria for PDD-NOS. The classifications on the ADOS and DSM-IV-TR were most similar, whereas the ADI-R classified subjects as autistic much more frequently. We further investigated the relationship of both FMRP and FMR1 mRNA to symptoms of autism in this cohort and found no significant relationship between the measures of autism and molecular features, including FMRP, FMR1 mRNA, and CGG repeat number.

scholarly journals Genome-wide DNA methylation profiling with MeDIP-seq using archived dried blood spots

2016 ◽  
Vol 8 (1) ◽  
Author(s):  
Nicklas H. Staunstrup ◽  
Anna Starnawska ◽  
Mette Nyegaard ◽  
Lene Christiansen ◽  
Anders L. Nielsen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dried Blood Spots ◽  
Blood Spots ◽  
Genome Wide ◽  
Dna Methylation Profiling ◽  
Methylation Profiling

scholarly journals Perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) and DNA methylation in newborn dried blood spots in the Upstate KIDS cohort

2021 ◽  
Vol 194 ◽  
pp. 110668
Author(s):  
Sonia L. Robinson ◽  
Xuehuo Zeng ◽  
Weihua Guan ◽  
Rajeshwari Sundaram ◽  
Pauline Mendola ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Perfluorooctane Sulfonate ◽  
Perfluorooctanoic Acid ◽  
Dried Blood Spots ◽  
Blood Spots

scholarly journals A Single Common Assay for Robust and Rapid Fragile X Mental Retardation Syndrome Screening From Dried Blood Spots

2018 ◽  
Vol 9 ◽  
Author(s):  
Vivienne J. Tan ◽  
Mulias Lian ◽  
Sultana M.H. Faradz ◽  
Tri I. Winarni ◽  
Samuel S. Chong
Keyword(s):  
Mental Retardation ◽  
Fragile X ◽  
Dried Blood Spots ◽  
Blood Spots ◽  
Fragile X Mental Retardation

scholarly journals Blood spots screening for identification of Fragile X Syndrome among intellectual disability students in Flores Island, INDONESIA

2013 ◽  
Vol 2013 (S1) ◽  
Author(s):  
Agustini Utari ◽  
Joyce Lo ◽  
Tzuhan Tong ◽  
Tri Indah Winarni ◽  
Sultana MH Faradz ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Blood Spots

Fragile X: A Family of Disorders

2010 ◽  
Author(s):  
Ann M. Mastergeorge ◽  
Jacky Au
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
X Chromosome ◽  
Culture Media ◽  
Fragile Site ◽  
Fragile X ◽  
Single Gene ◽  
Repeat Sequence ◽  
Full Mutation ◽  
Tissue Culture Media

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability known, and it is the most common single gene disorder associated with autism (Belmonte and Bourgeron 2006; Reddy 2005). It is caused by the lack or deficiency of the FMR1 protein, FMRP (Loesch et al. 2004b). The typical physical features of FXS include prominent ears, hyperextensible finger joints, flat feet, soft skin, and in adolescence and adulthood large testicles (macroorchidism) and a long face (Hagerman 2002b). The behavioral features include poor eye contact, hyperarousal to stimuli, anxiety, hyperactivity, attention deficit, impulsivity, hand stereotypies (such as hand biting and hand flapping), and social deficits including autism and autism spectrum disorder (ASD) (Budimirovic et al. 2006; Clifford et al. 2007; Hall et al. 2008b; Hatton et al. 2006b; Sullivan et al. 2007b). Fragile-X syndrome was first reported by Lubs (1969) in two brothers who had intellectual disability and the appearance of a marker X chromosome, which is a fragile site on their X chromosome. It was later detected that this fragile site on the X chromosome only occurred when the chromosomes were studied in a folate-deficient tissue culture media (Sutherland 1977). Therefore cytogenetic studies were utilized to document cases of FXS throughout the 1980s until the Fragile X Mental Retardation 1 gene (FMR1) was discovered in 1991 (Verkerk et al. 1991). The FMR1 gene was found to have a trinucleotide (CGG) repeat sequence at the 5’ untranslated region, with the normal range later determined to be up to 44 repeats, a gray zone of 45–54 repeats, a premutation of 55–200 repeats, and a full mutation range of more than 200 repeats (Maddalena et al. 2001). Those individuals with the full mutation have a deficit or absence of the FMR1 protein (FMRP) that causes the physical, behavioral, and cognitive features of FXS (Loesch et al. 2004b). Females with the full mutation have another X chromosome that is producing FMRP, depending on the activation ratio (AR) or the percentage of cells that have the normal X chromosome as the active X chromosome.

scholarly journals The Emergence of Effortful Control in Young Boys With Fragile X Syndrome

2018 ◽  
Vol 123 (2) ◽  
pp. 89-102 ◽  
Author(s):  
Marissa Robinson ◽  
Jessica Klusek ◽  
Michele D. Poe ◽  
Deborah D. Hatton ◽  
Jane E. Roberts
Keyword(s):  
Fragile X Syndrome ◽  
Effortful Control ◽  
Fragile X ◽  
Single Gene ◽  
Social Emotional Development ◽  
Social Emotional ◽  
Autism Symptoms ◽  
Emotional Outcomes ◽  
Preschool Boys ◽  
Molecular Measures

Abstract Effortful control, or the ability to suppress a dominant response to perform a subdominant response, is an early-emerging temperament trait that is linked with positive social-emotional development. Fragile X syndrome (FXS) is a single-gene disorder characterized by hallmark regulatory impairments, suggesting diminished effortful control. This study compared the development of effortful control in preschool boys with FXS (n = 97) and typical development (n = 32). Unlike their typical peers, the boys with FXS did not exhibit growth in effortful control over time, which could not be accounted for by adaptive impairments, FMR1 molecular measures, or autism symptoms. These results contribute to our understanding of the childhood phenotype of FXS that may be linked to the poor social-emotional outcomes seen in this group.

scholarly journals Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Emma K. Baker ◽  
Marta Arpone ◽  
Solange Aliaga Vera ◽  
Lesley Bretherton ◽  
Alexandra Ure ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Abilities ◽  
Fragile X ◽  
Autism Diagnostic Observation Schedule ◽  
Intellectual Functioning ◽  
Autism Spectrum ◽  
Aberrant Behavior Checklist ◽  
Age Appropriate ◽  
Maladaptive Behaviours ◽  
Age And Sex

Abstract Background Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55–199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours. Methods This study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours. Results Comparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. Conclusions Males with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.

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