FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: Insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States

Hantash, Feras M.; Goos, Dana; Crossley, Beryl; Anderson, Ben; Zhang, Ke; Sun, Weimin; Strom, Charles M.

doi:10.1097/gim.0b013e3181fa9fad

Cited by 96 publications

(65 citation statements)

References 46 publications

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“…It is interesting to note that from our study the female to male prevalence rate for the premutation is 2.05, in agreement with the predicted ratio described by Hagerman [31]. Although the size of the premutation alleles varied between 55 and 130 CGG repeats in females and between 56 and 125 CGG repeats in males, it is interesting to note that 70% of the premutation alleles contained <70 CGG repeats, in agreement with a recent report [32]. This may be of relevance for estimating the frequency of FMR1 related disorders in the general population since individuals with >70 repeats are more likely to have premutation disorders [75].…”

Section: Discussionsupporting

confidence: 93%

FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States

et al. 2012

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BackgroundPopulation screening for FMR1 mutations has been a topic of considerable discussion since the FMR1 gene was identified in 1991. Advances in understanding the molecular basis of fragile X syndrome (FXS) and in genetic testing methods have led to new, less expensive methodology to use for large screening endeavors. A core criterion for newborn screening is an accurate understanding of the public health burden of a disease, considering both disease severity and prevalence rate. This article addresses this need by reporting prevalence rates observed in a pilot newborn screening study for FXS in the US.MethodsBlood spot screening of 14,207 newborns (7,312 males and 6,895 females) was conducted in three birthing hospitals across the United States beginning in November 2008, using a PCR-based approach.ResultsThe prevalence of gray zone alleles was 1:66 females and 1:112 males, while the prevalence of a premutation was 1:209 females and 1:430 males. Differences in prevalence rates were observed among the various ethnic groups; specifically higher frequency for gray zone alleles in males was observed in the White group compared to the Hispanic and African-American groups. One full mutation male was identified (>200 CGG repeats).ConclusionsThe presented pilot study shows that newborn screening in fragile X is technically feasible and provides overall prevalence of the premutation and gray zone alleles in the USA, suggesting that the prevalence of the premutation, particularly in males, is higher than has been previously reported.

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Section: Discussionsupporting

confidence: 93%

FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States

et al. 2012

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“…We report interactive influences among biological, behavioral, and environmental factors in the development of psychopathology with mid-range CGG repeats, elevated child problem behavior and unmarried status conveying elevated risk in a sample subset. Given that 1 in 178 women carry the FMR 1 premutation (15), our data inform efforts towards improved identification and treatment to reduce, or ultimately prevent, adverse outcomes with women having mid-range repeats potentially at highest risk. Evidence from this study and others clearly indicate that females with an FMR 1 premutation are at risk for several disorders that should be considered as part of their routine health care.…”

Section: Discussionmentioning

confidence: 80%

“…Although premutation carriers were initially thought to be asymptomatic, a number of vulnerabilities have been reported, including elevated rates of mood and anxiety disorders (1,4–6), stress (5; 6), primary ovarian insufficiency (7–9), fragile X-associated tremor and ataxia syndrome (FXTAS) (9–11), and subtle differences in cognitive functions (12–14). Given approximately 1:178–209 women in the United States have the FMR 1 premutation (15; 16), understanding potential vulnerabilities is important to informing public health efforts.…”

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confidence: 99%

Trajectory and Predictors of Depression and Anxiety Disorders in Mothers With the FMR1 Premutation

Roberts

Tonnsen

McCary

et al. 2016

Biological Psychiatry

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Background Although the FMR1 premutation is associated with elevated prevalence of psychiatric disorders, the longitudinal course of symptoms has not been established. The present study followed a sample of women with the FMR1 premutation (1) to characterize the incidence, stability and predictors of mood and anxiety disorders across a 3-year period. Method Participants included 83 women with the FMR1 premutation (mean age=38.35) who completed the Structured Clinical Interview for the DSM-IV-I (2) at two time points, three years apart. Additional information was obtained regarding demographic, child, and biomedical (e.g. medication, menopause, CGG repeats) factors. Results We found increased prevalence of major depressive disorder (MDD) and anxiety disorders over time, with adverse outcomes predicted by complex interactions among biological, behavioral and environmental risk factors. Lifetime MDD increased from 46% to 54% and lifetime anxiety disorders from 28% to 35%. Mid-range CGG repeats, elevated child problem behavior and divorced marital status conveyed elevated risk for psychiatric diagnoses. Primary ovarian insufficiency was highly prevalent (41%) but did not account for elevated rates of psychiatric diagnoses. Medication use was highly reported (41%), particularly in women with MDD or anxiety, with selective serotonin reuptake inhibitors reported as the most commonly used medication across diagnostic groups. Conclusions The elevated prevalence of depression and anxiety in women with the FMR1 premutation is a clear and pressing concern given the frequent occurrence of the FMR1 premutation in the general community and the adverse outcomes – at both an individual and systems levels – associated with psychiatric disorders in this population.

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“…However, due to instability of the repeat across generations, there are large numbers of individuals who carry an expanded CGG repeat of between 55 and 200. These individuals are referred to as fragile X premutation (FPM) carriers, and occur in the general population with an estimated frequency of 1 in 209 females and 1 in 430 males [6,7]. Further expansion of the CGG repeat to greater than 200 in the offspring of FPM carriers leads to the full mutation, silencing of FMR1 expression and fragile X syndrome (FXS), the major known inherited cause of intellectual disability [4,8].…”

Section: Introductionmentioning

confidence: 99%

Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome

Berman

Buijsen

Usdin

et al. 2014

J Neurodevelop Disord

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Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5′-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca2+ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.

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FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: Insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States

Cited by 96 publications

References 46 publications

FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States

FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States

Trajectory and Predictors of Depression and Anxiety Disorders in Mothers With the FMR1 Premutation

Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome

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