Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors.

Duke University Medical Center, Durham, North Carolina 27710, USA.
Journal of Genetic Counseling (Impact Factor: 1.75). 09/2005; 14(4):249-70. DOI: 10.1007/s10897-005-4802-x
Source: PubMed

ABSTRACT These recommendations describe the minimum standard criteria for genetic counseling and testing of individuals and families with fragile X syndrome, as well as carriers and potential carriers of a fragile X mutation. The original guidelines (published in 2000) have been revised, replacing a stratified pre- and full mutation model of fragile X syndrome with one based on a continuum of gene effects across the full spectrum of FMR1 CGG trinucleotide repeat expansion. This document reviews the molecular genetics of fragile X syndrome, clinical phenotype (including the spectrum of premature ovarian failure and fragile X-associated tremor-ataxia syndrome), indications for genetic testing and interpretation of results, risks of transmission, family planning options, psychosocial issues, and references for professional and patient resources. These recommendations are the opinions of a multicenter working group of genetic counselors with expertise in fragile X syndrome genetic counseling, and they are based on clinical experience, review of pertinent English language articles, and reports of expert committees. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.

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    ABSTRACT: Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed 'full mutation' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term 'abnormal methylation' is used here to distinguish the DNA methylation induced by the expanded repeat from the 'normal methylation' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed 'premutation' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing.European Journal of Human Genetics advance online publication, 17 September 2014; doi:10.1038/ejhg.2014.185.
    European journal of human genetics: EJHG 09/2014; 23(4). DOI:10.1038/ejhg.2014.185 · 4.23 Impact Factor
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    ABSTRACT: The strongest association between FMR1 and the ovary in humans is the increased risk of premature ovarian failure (POF) in women who carry the premutation level of CGG repeats (55-199 CGGs). Research on the FMR1 gene has extended to other endpoints of relevance in the OB/GYN setting for women, including infertility and ovarian hormones. After reviewing the nomenclature changes that have occurred in recent years, this article reviews the evidence linking the length of the FMR1 repeat length to fertility and ovarian hormones (follicle stimulating hormone and anti-mullerian hormone as the primary methods to assess ovarian reserve in clinical settings). The literature is inconsistent on the association between the FMR1 trinucleotide repeat length and infertility. Elevated levels of follicle stimulating hormone have been found in women who carry the premutation; however the literature on the relationship between anti-mullerian hormone and the CGG repeat length are too disparate in design to make a summary statement. This article considers the implications of two transgenic mouse models (FXPM 130R and YAC90R) for theories on pathogenesis related to ovarian endpoints. Given the current screening/testing recommendations for reproductive age females and the variability of screening protocols in clinics, future research is recommended on pretest and posttest genetic counseling needs. Future research is also needed on ovarian health measurements across a range of CGG repeat lengths in order to interpret FMR1 test results in reproductive age women; the inconsistencies in the literature make it quite challenging to advise women on their risks related to FMR1 repeat length.
    Frontiers in Genetics 07/2014; 5:195. DOI:10.3389/fgene.2014.00195
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    ABSTRACT: The National Society of Genetic Counselors (NSGC) supports the development of practice recommendations (guidelines) in the field of genetic counseling. This paper reviews the basic components of NSGC genetic counseling practice recommendations as well as the process for formal adoption of such documents, as approved by the Board of Directors of the NSGC.
    Journal of Genetic Counseling 01/2003; 12(4). DOI:10.1023/A:1023995904543 · 1.75 Impact Factor

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