Fragile X syndrome (FXS) is one of several clinical disorders associated with mutations in the X-linked Fragile X Mental Retardation-1 (FMR1) gene. With evolving knowledge about the phenotypic consequences of FMR1 transcription and translation, sharp clinical distinctions between pre- and full mutations have become more fluid. The complexity of the issues surrounding genetic testing and management of FMR1-associated disorders has increased; and several aspects of genetic counseling for FMR1 mutations remain challenging, including risk assessment for intermediate alleles and the widely variable clinical prognosis for females with full mutations. FMR1 mutation testing is increasingly being offered to women without known risk factors, and newborn screening for FXS is underway in research-based pilot studies. Each diagnosis of an FMR1 mutation has far-reaching clinical and reproductive implications for the extended family. The interest in large-scale population screening is likely to increase due to patient demand and awareness, and as targeted pharmaceutical treatments for FXS become available over the next decade. Given these developments and the likelihood of more widespread screening, genetic counselors across a variety of healthcare settings will increasingly be called upon to address complex diagnostic, psychosocial, and management issues related to FMR1 gene mutations. The following guidelines are intended to assist genetic counselors in providing accurate risk assessment and appropriate educational and supportive counseling for individuals with positive test results and families affected by FMR1-associated disorders.
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Adams, P., Adams, J., Nguyen, D., Hessl, D., Brunberg, J., et al. (2010). Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers. American Journal of Medical Genetics B, Neuropsychiatric Genetics, 153B(3), 775–785.
Allen, E. G., Sullivan, A. K., Marcus, M., Small, C., Dominguez, C., et al. (2007). Examination of reproductive aging milestones among women who carry the FMR1 premutation. Human Reproduction, 22(8), 2142–2152.
American College of Obstetricians and Gynecologists Committee on Genetics. (2010). ACOG Committee Opinion No.469: Carrier screening for fragile X syndrome. Obstetrics & Gynecology, 116, 1008–1010.
Aziz, M., Stathopulu, E., Callias, M., Taylor, C., Turk, J., et al. (2003). Clinical features of boys with fragile X premutations and intermediate alleles. American Journal of Medical Genetics, 121B(1), 119–127.
Bailey, D. B., Jr., Skinner, D., & Sparkman, K. L. (2003). Discovering fragile X syndrome: family experiences and perceptions. Pediatrics, 111(2), 407–416.
Bear, M. F., Huber, K. M., & Warren, S. T. (2004). The mGluR theory of fragile X mental retardation. Neuroscience, 27(7), 370–377.
Bennett, C. E., Conway, G. S., Macpherson, J. N., Jacobs, P. A., & Murray, A. (2010). Intermediate sized CGG repeats are not a common cause of idiopathic premature ovarian failure. Human Reproduction, 25(5), 1335–1338.
Bodega, B., Bione, S., Dalpra, L., Toniolo, D., Ornaghi, F., et al. (2006). Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation. Human Reproduction, 21(4), 952–957.
Braden, M. L. (1996). Fragile—Handle with care: Understanding fragile X syndrome. Chapel Hill: Avanta Publishing Company.
Chen, L., Hadd, A., Sah, S., Filipovic-Sadic, S., Krosting, J., et al. (2010). An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for Southern blot analysis. Journal of Molecular Diagnosis, 12, 589–600.
Chen, L., Hadd, A. G., Houghton, J. F., Filipovic-Sadic, S., Zhang, W., et al. (2011). High-resolution methylation polymerase chain reaction for fragile X analysis: evidence for novel FMR1 methylation patterns undetected in Southern blot analyses. Genetics in Medicine, 13(6), 528–538.
Coffey, S. M., Cook, K., Tartaglia, N., Tassone, F., Nguyen, D. V., et al. (2008). Expanded clinical phenotype of women with the FMR1 premutation. American Journal of Medical Genetics A, 146A, 1009–1016.
Crawford, D. C., Acuna, J. M., & Sherman, S. L. (2001). FMR1 and the fragile X syndrome: human genome epidemiology review. Genetics in Medicine, 3(5), 359–371.
Cronister, A., Schreiner, R., Wittenberger, M., Amiri, K., Harris, K., & Hagerman, R. J. (1991). Heterozygous fragile X females: historical, physical, cognitive, and cytogenetic features. American Journal of Medical Genetics, 38(2–3), 269–274.
Cronister, A., Teicher, J., Rohlfs, E. M., Donnenfeld, A., & Hallam, S. (2008). Prevalence and instability of fragile X alleles: implications for offering fragile X prenatal diagnosis. Obstetrics and Gynecology, 111(3), 596–601.
De Vries, B. B. A., Wiegers, A. M., Smits, A. P. T., Mohkamsing, S., Duivenvoorde, J. H., et al. (1996). Mental status of females with an FMR-1 gene full mutation. American Journal of Human Genetics, 58(5), 1025–1032.
Dombrowski, C., Levesque, S., Morel, M. L., Rehel, R., Cote, J. S., et al. (2002). Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Human Molecular Genetics, 11(4), 371–378.
Ennis, S., Murray, A., Youings, S., Brightwell, G., Herrick, D., et al. (2006). An investigation of FRAXA intermediate allele phenotype in a longitudinal sample. Annals of Human Genetics, 70(2), 170–180.
Filipovic-Sadic, S., Sah, S., Chen, L., Krosting, J., Sekinger, E., et al. (2010). A novel FMR1 PCR method for the routine detection of low abundance expanded alleles and full mutations in fragile X syndrome. Clinical Chemistry, 56(3), 399–408.
Garcia-Arocena, D., & Hagerman, P. J. (2010). Advances in understanding the molecular basis of FXTAS. Human Molecular Genetics, 19(R1), R83–89.
Hagerman, R. J. (2002). The physical and behavioral phenotype. In R. J. Hagerman & P. J. Hagerman (Eds.), Fragile X syndrome, diagnosis treatment, and research (3rd ed., pp. 3–109). Baltimore: Johns Hopkins University Press.
Hagerman, P. J., & Hagerman, R. J. (2004). The fragile-X premutation: a maturing perspective. American Journal of Human Genetics, 74(5), 805–816.
Hagerman, R. J., Leehey, M., Heinrichs, W., Tassone, F., Wilson, R., et al. (2001). Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology, 57(1), 127–130.
Hagerman, R., Berry-Kravis, E., Kaufmann, W., Ono, M., Tartaglia, N., et al. (2009). Advances in the treatment of fragile X syndrome. Pediatrics, 123(1), 378–390.
Hessl, D., Tassone, F., Loesch, D. Z., Berry-Kravis, E., Leehey, M. A., et al. (2005). Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation. American Journal of Medical Genetics B, Neuropsychiatric Genetics, 139B(1), 115–121.
Hill, M. K., Archibald, A. D., Cohen, J., & Metcalfe, S. A. (2010). A systematic review of population screening for fragile X syndrome. Genetics in Medicine, 12(7), 396–410.
Hunter, J., Rohr, J., & Sherman, S. (2010). Co-occurring diagnoses among FMR1 premutation allele carriers. Clin Genet, 77(4), 374–381.
Jacquemont, S., Hagerman, R. J., Leehey, M., Grigsby, J., Zhang, L., et al. (2003). Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. American Journal of Human Genetics, 72(4), 869–878.
Keysor, C. S., & Mazzocco, M. M. (2002). A developmental approach to understanding fragile X syndrome in females. Microscopy Research and Technique, 57(3), 179–186.
Lachiewicz, A., Dawson, D., Spiridigliozzi, G., Cuccaro, M., Lachiewicz, M., & McConkie-Rosell, A. (2010). Indicators of anxiety and depression in women with the fragile X premutation: assessment of a clinical sample. Journal of Intellectual Disability Research, 54(7), 597–610.
Levesque, S., Dombrowski, C., Morela, M. L., Rehel, R., Cote, J. S., Bussieres, J., Morgan, K., & Rousseau, F. (2009). Screening and instability of FMR1 alleles in a prospective sample of 24,449 mother–newborn pairs from the general population. Clinical Genetics, 76(6), 511–523.
Loesch, D. Z., Godler, D. E., Khaniani, M., Gould, E. G., et al. (2009). Linking the FMR1 alleles with small CGG expansions with neurodevelopmental disorders: preliminary data suggest an involvement of epigenetic mechanisms. American Journal of Medical Genetics, 149A(10), 2306–2310.
Loesch, D. Z., Khaniani, M. S., Slater, H. R., Rubio, J. P., Bui, Q. M., et al. (2009). Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism. Clinical Genetics, 76(5), 471–476.
Lubs, H. A. (1969). A marker X chromosome. American Journal of Human Genetics, 21, 231–244.
Lyon, E., Laver, T., Yu, P., Jama, M., Young, K., et al. (2010). A simple, high-throughput assay for Fragile X expanded alleles using triple repeat primed PCR and capillary electrophoresis. Journal of Molecular Diagnosis, 12(4), 505–511.
Musci, T. J., & Caughey, A. B. (2005). Cost-effectiveness analysis of prenatal population-based fragile X carrier screening. American Journal of Obstetrics and Gynecology, 192(6), 1905–1912.
Nolin, S. L., Brown, W. T., Glicksman, A., Houck, G. E., Gargano, A. D., Sullivan, A., et al. (2003). Expansion of the fragile X CGG repeat in females with premutations or intermediate alleles. American Journal of Human Genetics, 72, 454–464.
Nolin, S. L., Glicksman, A., Ding, X., Ersalesi, N., Brown, W. T., et al. (2011). Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenatal Diagnosis, 31(10), 925–931.
Ogren, M., & Lombroso, P. (2008). Reversing the effects of fragile X syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 47(8), 863–867.
Rodriguez-Revenga, L., Madrigal, I., Pagonabarraga, J., Xunclà, M., Badenas, C., et al. (2009). Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. European Journal of Human Genetics, 17(10), 1359–1362.
Rousseau, F., Heitz, D., Tarleton, J., MacPherson, J., Malgran, H., et al. (1994). A multicenter study on genotype–phenotype correlation in the fragile X syndrome, using direct diagnosis with the probe STB 12.3. The first 2,253 cases. American Journal of Human Genetics, 55(2), 225–237.
Rousseau, F., Rouillard, P., Khandjian, E. W., & Morgan, K. (1995). Prevalence of carriers of premutation-size alleles of the FMR1 gene and implications for the population genetics of the fragile X syndrome. American Journal of Human Genetics, 57(5), 1006–1018.
Seltzer, M. M., Baker, M. W., Hong, J., Maenner, M., Greenberg, J., et al. (2012). Prevalence of CGG expansions of the FMR1 gene in a US population-based sample. American Journal of Medical Genetics Part B, 159B, 589–597.
Sherman, S. L. (2000). Premature ovarian failure in the fragile X syndrome. American Journal of Medical Genetics, 97(3), 189–194.
Sherman, S., Pletcher, B. A., & Driscoll, D. A. (2005). ACMG practice guideline. FragileX syndrome: diagnostic and carrier testing. Genetics in Medicine, 7(9), 584–587.
Spector, E.B. &, Kronquist, K. (2006 edition). Technical Standards and Guidelines for Fragile X Testing: A Revision to the Disease-Specific Supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. Fragile X Molecular Working Group 2005 for the Quality Assurance Committee of the American College of Medical Genetics. Retrieved from http://www.acmg.net/Pages/ACMG_Activities/stds-2002/stdsmenu-n.htm
Toledano-Alhadef, H., Basel-Vanagaite, L., Magal, N., Davidov, B., Ehrlich, S., et al. (2001). Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. American Journal of Human Genetics, 69, 352–360.
Tsafrir, A., Altarescu, G., Margalioth, E., Brooks, B., Renbaum, P., et al. (2010). PGD for fragile X syndrome: ovarian function is the main determinant of success. Human Reproduction, 25(10), 2629–2636.
Wittenberger, M. D., Hagerman, R. J., Sherman, S. L., McConkie-Rosell, A., Welt, C. K., et al. (2007). The FMR1 premutation and reproduction. Fertility and Sterility, 87(3), 456–65.
Yrigollen, C. M., Durbin-Johnson, B., Gane, L., Nelson, D. L., Hagerman, R., et al. (2012).AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genetics in Medicine. doi:10.1038/gim.2012.34.[Epubaheadofprint].
The practice guidelines of the National Society of Genetic Counselors (NSGC) are developed by members of the NSGC to assist genetic counselors and other health care providers in making decisions about appropriate management of genetic concerns; including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue, and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the NSGC practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are only current as of their publication date, and are subject to change without notice as advances emerge. In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health care provider’s best medical judgment based on the clinical circumstances of a particular patient or patient population. Practice guidelines are published by NSGC for educational and informational purposes only, and NSGC does not “approve” or “endorse” any specific methods, practices, or sources of information.
© 2011 National Society of Genetic Counselors. All rights reserved. This document may not, in whole or in part, be reproduced, copied or disseminated, entered into or stored in a computer database or retrieval system, or otherwise utilized without the prior written consent of the NSGC.
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Finucane, B., Abrams, L., Cronister, A. et al. Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the National Society of Genetic Counselors. J Genet Counsel 21, 752–760 (2012). https://doi.org/10.1007/s10897-012-9524-8
- Fragile X
- Genetic counseling