scholarly journals Is FMR1 CGG Repeat Number Polymorphism Associated With Phenotypic Variation in the General Population? Report From a Cohort of 5,499 Adults

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinkuk Hong ◽  
Leann DaWalt ◽  
Mei Wang Baker ◽  
Elizabeth M. Berry-Kravis ◽  
Marsha R. Mailick
Keyword(s):  
High School ◽  
General Population ◽  
Fragile X ◽  
Repeat Length ◽  
College Graduation ◽  
Repeat Number ◽  
Cgg Repeat ◽  
Age At Menopause ◽  
Cgg Repeats ◽  
Biological Children

FMR1 CGG repeat length was assayed in 5499 research participants (2637 men and 2862 women) in the Wisconsin Longitudinal Study (WLS), a population-based cohort. Most past research has focused on clinically-ascertained individuals with expansions in CGG repeats, either those with fragile X syndrome (> 200 CGG repeats), the FMR1 premutation (55–200 repeats), or in the gray zone (variously defined as 45–54 or 41–54 repeats). In contrast, the WLS is a unique source of data that was obtained from an unselected cohort of individuals from the general population for whom FMR1 CGG repeat length was assayed. The WLS is a random sample of one-third of all high school seniors in the state of Wisconsin in 1957. The most recent round of data collection was in 2011; thus, the study spanned over 50 years. Saliva samples were obtained from 69% of surviving members of the cohort in 2008 and 2011, from which CGG repeats were assayed. With one exception, the CGG repeat length of all members of this cohort was below 100 (ranging from 7 to 84). The present study evaluated the genotype-phenotype associations of CGG repeat number and IQ, college graduation, age at menopause, number of biological children, having a child with intellectual or developmental disabilities, and the likelihood of experiencing an episode of depression during adulthood. Linear and curvilinear effects were probed. Although effect sizes were small, significant associations were found between CGG repeat length and high school IQ score, college graduation, number of biological children, age at menopause, and the likelihood of having an episode of depression. However, there was no significant association between repeat length and having a child diagnosed with an IDD condition. This study demonstrates a continuum of phenotype effects with FMR1 repeat lengths and illustrates how research inspired by a rare genetic condition (such as fragile X syndrome) can be used to probe genotype-phenotype associations in the general population.

scholarly journals FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1780
Author(s):  
Mark Roth ◽  
Lucienne Ronco ◽  
Diego Cadavid ◽  
Blythe Durbin-Johnson ◽  
Randi J. Hagerman ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Peripheral Blood ◽  
Fragile X ◽  
Repeat Expansion ◽  
Repeat Number ◽  
Cgg Repeat ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Fmr1 Mrna

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

scholarly journals Genetic and Environmental Influences on Self-Reported Cognitive Functioning: Associations of Diverse Measures of Stress across the FMR1 CGG Repeat Range

2020 ◽  
Author(s):  
Nell Maltman ◽  
Leann Smith DaWalt ◽  
Jinkuk Hong ◽  
Mei Wang Baker ◽  
Elizabeth M Berry-Kravis ◽  
...  
Keyword(s):  
Executive Function ◽  
Cognitive Function ◽  
Executive Functioning ◽  
Life Events ◽  
Perceived Stress ◽  
Repeat Length ◽  
Repeat Number ◽  
Cgg Repeat ◽  
Memory Problems ◽  
Cgg Repeats

Abstract Background : The FMR1 gene is essential for neural development and healthy synaptic function. The modal number of CGG repeats in FMR1 is 30, but the range is large with the reported copy number extending down to as few as 6 CGGs and up to over 200 CGGs, conferring fragile X syndrome. Prior work suggests that behavioral phenotypes, including cognitive function, may vary along the continuum of the FMR1 CGG repeat range. Stress may negatively influence cognitive function; however, it is not known whether FMR1 -related variability (i.e., CGG repeat length), in addition to stress, independently influences cognitive function across the CGG range. Methods : Participants included 1275 mothers who had CGGs ranging from 18 to 123 repeats. Participants completed self-report measures of executive function (BRIEF-A), memory, subjective stress (i.e., perceived stress), and objective stress (i.e., number of life events, parenting a child with a disability). Stress and FMR1 -related variability (i.e., CGG repeat length) were examined as predictors of self-reported executive function and memory difficulty. Results : Each measure of stress (i.e., perceived stress, life events, and parenting a child with a disability) significantly predicted greater self-reported difficulties in executive function and the likelihood of memory problems, net of age and level of education. Additionally, above and beyond stress effects, CGG repeat number significantly predicted executive functioning and memory difficulties. There was a linear association of CGG repeat number with executive functioning limitations. The association of CGGs with memory difficulties was curvilinear, with participants in the premutation range having the greatest likelihood of reporting such difficulties. Conclusions : These findings suggest that CGG repeat length confers independent contributions to self-reported executive function difficulty and memory problems over and above indices of stress, suggesting additive effects of genetic variation and environmental exposure. Keywords : Stress, Cognitive Function, Executive Function, Memory, FMR1 , CGG Repeats

CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS)

2007 ◽  
Vol 144B (4) ◽  
pp. 566-569 ◽  
Author(s):  
Flora Tassone ◽  
John Adams ◽  
Elizabeth M. Berry-Kravis ◽  
Susannah S. Cohen ◽  
Alfredo Brusco ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Fragile X ◽  
Repeat Length ◽  
Cgg Repeat ◽  
Ataxia Syndrome

scholarly journals CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome

2008 ◽  
Vol 107 (6) ◽  
pp. 1671-1682 ◽  
Author(s):  
Judith R. Brouwer ◽  
Karin Huizer ◽  
Lies-Anne Severijnen ◽  
Renate K. Hukema ◽  
Robert F. Berman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X ◽  
Repeat Length ◽  
Cgg Repeat ◽  
Ataxia Syndrome

scholarly journals Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Jessica Klusek ◽  
Amanda Fairchild ◽  
Carly Moser ◽  
Marsha R. Mailick ◽  
Angela John Thurman ◽  
...  
Keyword(s):  
Family History ◽  
Neurodegenerative Disease ◽  
Cognitive Skills ◽  
Fragile X ◽  
Repeat Length ◽  
Syntactic Complexity ◽  
Cgg Repeat ◽  
Age Related ◽  
Increased Risk ◽  
History Of

Abstract Background Women who carry a premutation allele of the FMR1 gene are at increased vulnerability to an array of age-related symptoms and disorders, including age-related decline in select cognitive skills. However, the risk factors for age-related decline are poorly understood, including the potential role of family history and genetic factors. In other forms of pathological aging, early decline in syntactic complexity is observed and predicts the later onset of neurodegenerative disease. To shed light on the earliest signs of degeneration, the present study characterized longitudinal changes in the syntactic complexity of women with the FMR1 premutation across midlife, and associations with family history of fragile X-associated tremor/ataxia syndrome (FXTAS) and CGG repeat length. Methods Forty-five women with the FMR1 premutation aged 35–64 years at study entry participated in 1–5 longitudinal assessments spaced approximately a year apart (130 observations total). All participants were mothers of children with confirmed fragile X syndrome. Language samples were analyzed for syntactic complexity and participants provided information on family history of FXTAS. CGG repeat length was determined via molecular genetic testing. Results Hierarchical linear models indicated that women who reported a family history of FXTAS exhibited faster age-related decline in syntactic complexity than those without a family history, with that difference emerging as the women reached their mid-50 s. CGG repeat length was not a significant predictor of age-related change. Conclusions Results suggest that women with the FMR1 premutation who have a family history of FXTAS may be at increased risk for neurodegenerative disease, as indicated by age-related loss of syntactic complexity. Thus, family history of FXTAS may represent a personalized risk factor for age-related disease. Follow-up study is needed to determine whether syntactic decline is an early indicator of FXTAS specifically, as opposed to being a more general age-related cognitive decline associated with the FMR1 premutation.

scholarly journals Analysis of unstable DNA sequence in FMR1 gene in Polish families with fragile X syndrome.

1996 ◽  
Vol 43 (2) ◽  
pp. 383-388
Author(s):  
M Milewski ◽  
M Zygulska ◽  
J Bal ◽  
W H Deelen ◽  
E Obersztyn ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Dna Sequence ◽  
Clinical Features ◽  
Fragile Site ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Repeat Number ◽  
Full Mutation ◽  
Cgg Repeats ◽  
Large Expansion

The unstable DNA sequence in the FMR1 gene was analyzed in 85 individuals from Polish families with fragile X syndrome in order to characterize mutations responsible for the disease in Poland. In all affected individuals classified on the basis of clinical features and expression of the fragile site at X(q27.3) a large expansion of the unstable sequence (full mutation) was detected. About 5% (2 of 43) of individuals with full mutation did not express the fragile site. Among normal alleles, ranging in size from 20 to 41 CGG repeats, allele with 29 repeats was the most frequent (37%). Transmission of premutated and fully mutated alleles to the offspring was always associated with size increase. No change in repeat number was found when normal alleles were transmitted.

scholarly journals Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa)

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 136
Author(s):  
Karen Kengne Kamga ◽  
Séraphin Nguefack ◽  
Khuthala Minka ◽  
Edmond Wonkam Tingang ◽  
Alina Esterhuizen ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Sub Saharan Africa ◽  
Rural Setting ◽  
Premature Menopause ◽  
Molecular Testing ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Cgg Repeats

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family. A total of 46 individuals were tested for FXS; among them, 58.70% (n = 27) were females. The mean age was 9.4 (±5) years for children and 45.9 (±15.9) years for adults. Pedigree analysis suggested that the founder of these families was likely a normal transmitting male. Four out of 19 males with clinical ID were confirmed to have a full mutation for FXS, while 14/27 females had a pathologic CGG expansion (>56 CGG repeats) on one of their X chromosomes. Two women with premature menopause were confirmed of being carriers of premutation (91 and 101 CGG repeats). We also identified maternal alleles (91 and 126 CGG repeats) which expanded to a full mutation in their offspring (>200 CGG repeats). This study is a rare report on FXS from Africa and illustrates the case scenario of implementing genetic medicine for a neurogenetic condition in a rural setting.

scholarly journals Genetic and Environmental Influences on Self-Reported Cognitive Functioning: Associations of Diverse Measures of Stress across the FMR1 CGG Repeat Range

2020 ◽  
Author(s):  
Nell Maltman ◽  
Leann Smith DaWalt ◽  
Jinkuk Hong ◽  
Mei Wang Baker ◽  
Elizabeth M Berry-Kravis ◽  
...  
Keyword(s):  
Executive Function ◽  
Cognitive Function ◽  
Life Events ◽  
Perceived Stress ◽  
Synaptic Function ◽  
Repeat Length ◽  
Cgg Repeat ◽  
Memory Problems ◽  
Cgg Repeats ◽  
Child With A Disability

Abstract Background: The FMR1 gene is essential for neural development and healthy synaptic function. The modal number of CGG repeats in FMR1 is 30, but the range is large with the reported copy number extending down to as few as 6 CGGs and up to over 200 CGGs. Prior work suggests that behavioral phenotypes, including cognitive function, may vary along the continuum of the FMR1 CGG repeat range. Stress also negatively influences cognitive function; however, it is not known whether FMR1-related variability (i.e., CGG repeat length), in addition to stress, independently influences cognitive function across the CGG range. Methods: Participants included 1275 mothers who had between 18 and 123 CGG repeats. Participants completed self-report measures of executive function (BRIEF-A), memory, subjective stress (i.e., perceived stress), and objective stress (i.e., number of life events, parenting a child with a disability). Stress and CGG repeat length were examined as predictors of self-reported executive function and memory difficulty. Results: Each measure of stress (i.e., perceived stress, life events, and parenting a child with a disability) significantly predicted greater self-reported difficulties in executive function and the likelihood of memory problems, net of age and level of education. Additionally, above and beyond stress effects, CGG repeat number significantly predicted executive functioning and memory difficulties. Conclusions: These findings suggest that CGG repeat length confers independent contributions to self-reported executive function difficulty and memory problems over and above indices of stress, suggesting additive effects of genetic variation and environmental exposure.

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