Journal of Genetic Counseling

, Volume 21, Issue 6, pp 752–760 | Cite as

Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the National Society of Genetic Counselors

  • Brenda Finucane
  • Liane Abrams
  • Amy Cronister
  • Alison D. Archibald
  • Robin L. Bennett
  • Allyn McConkie-Rosell
Professional Issues


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.


Fragile X FMR1 FXTAS FXPOI Genetic counseling 



  1. 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.Google Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. Bailey, D. B., Jr., Skinner, D., & Sparkman, K. L. (2003). Discovering fragile X syndrome: family experiences and perceptions. Pediatrics, 111(2), 407–416.PubMedCrossRefGoogle Scholar
  6. Bear, M. F., Huber, K. M., & Warren, S. T. (2004). The mGluR theory of fragile X mental retardation. Neuroscience, 27(7), 370–377.Google Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. Braden, M. L. (1996). Fragile—Handle with care: Understanding fragile X syndrome. Chapel Hill: Avanta Publishing Company.Google Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. Garcia-Arocena, D., & Hagerman, P. J. (2010). Advances in understanding the molecular basis of FXTAS. Human Molecular Genetics, 19(R1), R83–89.PubMedCrossRefGoogle Scholar
  21. 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.Google Scholar
  22. Hagerman, P. J., & Hagerman, R. J. (2004). The fragile-X premutation: a maturing perspective. American Journal of Human Genetics, 74(5), 805–816.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. Hunter, J., Rohr, J., & Sherman, S. (2010). Co-occurring diagnoses among FMR1 premutation allele carriers. Clin Genet, 77(4), 374–381.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. Lubs, H. A. (1969). A marker X chromosome. American Journal of Human Genetics, 21, 231–244.PubMedGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. Sherman, S. L. (2000). Premature ovarian failure in the fragile X syndrome. American Journal of Medical Genetics, 97(3), 189–194.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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
  47. 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.Google Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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].

Copyright information

© National Society of Genetic Counselors, Inc. 2012

Authors and Affiliations

  • Brenda Finucane
    • 1
  • Liane Abrams
    • 2
  • Amy Cronister
    • 3
  • Alison D. Archibald
    • 4
  • Robin L. Bennett
    • 5
  • Allyn McConkie-Rosell
    • 6
  1. 1.Genetic Services at ElwynElwynUSA
  2. 2.National Fragile X FoundationWalnut CreekUSA
  3. 3.Integrated GeneticsPhoenixUSA
  4. 4.Victorian Clinical Genetics ServicesMelbourneAustralia
  5. 5.Division of Medical GeneticsUniversity of Washington Medical CenterSeattleUSA
  6. 6.Division of Medical GeneticsDuke University Medical CenterDurhamUSA

Personalised recommendations