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: 2.24). 09/2005; 14(4):249-70. DOI: 10.1007/s10897-005-4802-x
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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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    • "The National Society of Genetic Counselors and the Genetics Committee of the American College of Obstetrics and Gynecology support this recommendation (ACOG Committee of Genetics, 2010; Finucane et al., 2012), as did participants in a collaborative project between the MIND Institute Fragile X Research and Treatment Center at the University of California at Davis, the National Fragile X Foundation, and the Centers for Disease Control and Prevention (McConkie-Rosell et al., 2007). Some authors have called for further research to explore potential genetic counseling issues for women ascertained in an infertility setting, including the lack of prior experience with individuals with FXS, the impact of unexpected findings on risk perceptions, regret or anger that testing was not considered earlier in the infertility evaluation process, and the shift of focus to include extended family (McConkie-Rosell et al., 2005, 2007; Wittenberger et al., 2007). "
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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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    • "As we can see, 190 ICs (190/1105 = 17.2%) had normal intelligence and they were referred because they had a family history of ID, or because they had an ovarian failure or there was suspicion of FXTAS, and all were found to be carriers of a PM. The diagnosis of new FX families with these selection criteria confirms what has been recommended by the FX American Expert Working Group [26] in the sense that all these reasons for referrals are associated with a high rate of identification of affected individuals and carriers. "
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    ABSTRACT: Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of <59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling.
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    • "It is estimated that 1 in 157 females [Berkenstadt et al., 2007] and 1 in 755 males [Rousseau et al., 1996] are carriers of the pre-mutation. The current approach to identifying carriers of FXS is to offer genetic testing to individuals with a family history of FXS or undiagnosed intellectual disability [McConkie-Rosell et al., 2005; Sherman et al., 2005]. However, this approach is limited by issues around dissemination of genetic risk information in families [van Rijn et al., 1997] and its reliance on the diagnosis of an affected individual to make relatives aware of their risk. "
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    ABSTRACT: Population carrier screening for fragile X syndrome can provide women with information about their risk of having a child with fragile X syndrome and their risk of fragile X-associated primary ovarian insufficiency and fragile X-associated tremor ataxia syndrome. Few studies have explored women's decisions when offered carrier screening for fragile X syndrome. Interviews were conducted with 31 women who participated in a pilot study offering carrier screening to non-pregnant women. A qualitative approach was used to gain an in-depth understanding of women's experiences and examine their decision-making processes, including women who were tested and those who decided not to be tested. The decision-making process occurred in two phases. In the first phase, the participant's reproductive stage of life and experience with illness and disability were major factors influencing whether she would consider screening. In the second phase of decision-making, participants' perceptions of the value of knowing their carrier status was the most notable factor for influencing whether a woman actually had the carrier test. Some women appreciated having time for deliberation and those who were tested did not express regret about their decision. Our findings support offering carrier screening for fragile X syndrome to non-pregnant women and suggest that women from the general population will have specific informational and counseling needs when offered carrier testing. This study highlights the unique challenges encountered by women from the general population when making a decision about testing for fragile X syndrome carrier status and illustrates the importance of understanding how women make decisions.
    American Journal of Medical Genetics Part A 12/2009; 149A(12):2731-8. DOI:10.1002/ajmg.a.33122 · 2.16 Impact Factor
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