Historically, methods for FMR1 carrier screening have either suffered from poor accuracy or have been too onerous to be
broadly adopted. New advances in FMR1 PCR, however, offer rapid, reliable, and high throughput technologies that can
support cost-effective screening and provide precise molecular profiling to identify carriers at risk for conceiving
children with fragile X syndrome. Recent studies indicate that the FMR1 carrier frequency in women is 1:178 to 1:250
[1,2,3]; meaning that there are up to 880,000 female carriers in the US alone. The overwhelming majority
of these carriers are undiagnosed. Further, all female carriers are at risk for having an affected child due to the X-linked transmission of the FMR1 gene.
Indeed, the incidence of at-risk carriers is actually higher than any of the other three disorders currently recommended for carrier screening by the
American College of Obstetricians and Gynecologists (ACOG). ACOG already recommends testing for families with a history of fragile X or mental
retardation, or for any woman that requests it following genetic counseling , but these recommendations
fall well short of detecting all carriers. In fact, the largest proportion of fragile X births are from families without index cases. With the advancement in
testing technology, fragile X now meets four of the five criteria for general carrier testing [14,23].
Specifically, the disorder is considered a significant health problem, and screening can be robust, simple, and cost-effective.
There are arguments against carrier screening which do bear merit, such as the type of counseling patients at risk with fragile X-associated disorders should
receive. As a result, fragile X carrier screening is a complex issue, but recent technological advances are no longer a hurdle to routine screening, and
thus the issue deserves more extensive dialog among health care professionals.
- • Describe the implications of FMR1 carrier screening in enabling more informed patient decisions and supporting population-based health initiatives
- • Discuss new PCR approaches that address the technological challenges of carrier screening
- • Discuss the challenges of implementing carrier screening, e.g. cost, throughput, complexity in FMR1 disorder age-onset and presentation, ethical dilemmas, etc.
1. 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 FM, Goos DM, Crossley B, Anderson B, Zhang K, Sun W, Strom CM. Genet Med. 2011 Jan;13(1):39-45.
*The authors survey a broad large cohort of samples not submitted for fragile X testing in order to gain estimates on an unbiased population frequency. They found a premutation carrier frequency of 1:178 in women and 1:400 in men. These frequencies are similar to or exceed thresholds established for ACOG recommended screening programs in other diseases such as Tay-Sachs, Canavan’s and Cystic Fibrosis.
2. Prevalence and instability of fragile X alleles: implications for offering fragile X prenatal diagnosis
Cronister A, Teicher J, Rohlfs EM, Donnenfeld A, Hallam S. Obstet Gynecol 2008;111:596–601;
3. Carrier Screening for Fragile X syndrome.
Committee on Genetics. ACOG 2010; 116 (4): 1008-1010
** This ACOG Committee Opinion in 2010 recommends testing for fragile X syndrome to include women with family history of fragile X-related disorders, unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency as candidates for genetic counseling and fragile X premutation carrier screening. Moreover, the Opinion stipulates access to testing for any woman who requests it regardless of family history.
4. Molecular fragile X screening in normal populations.
Spence WC, Black SH, Fallon L, et al. Am J Med Genet 1996;64:181–183;
5. Fragile-X Carrier Screening and the Prevalence of Premutation and Full-Mutation Carriers in Israel.
Toledano-Alhadef H et al. Am J Hum Genet 2001; 69(2): 351–360
**The authors report outcomes of testing 14,334 Israeli women of childbearing age for fragile X carrier status between 1992 and 2000. These women were either preconceptional or pregnant and had no family history of mental retardation. They identified 207 carriers of an allele with more than 50 repeats and three asymptomatic women carried the full-mutation allele. Among the premutation and full-mutation carriers, 177 prenatal diagnoses were performed. Expansion occurred in 30 fetuses, 5 of which had an expansion to the full mutation. The authors recommended wide-scale screening to identify female carriers.
6. Fragile X syndrome carrier screening in the prenatal genetic counseling setting.
Cronister A et al. Genet Med 2005; 7(4):246–250
7. Fragile X syndrome: diagnostic and carrier testing.
Sherman S et al. Genet Med 2005; 7(8): 584-587
**This publication represents the revised fragile X testing guidelines for the American College of Medical Geneticists and describes and overview of the disease and laboratory practice for fragile X testing.
8. Cost-effectiveness analysis of prenatal population-based fragile X carrier screening.
Musci TJ et al. Am J Obstet Gynecol 2005; 192(6):1905–1912
9. A model for offering carrier screening for fragile X syndrome to nonpregnant women: results from a pilot study.
Metcalfe S et al. Genet Med 2008; 10(7):525-535
10. High-risk fragile x screening in Guatemala: use of a new blood spot polymerase chain reaction technique.
Toledano-Alhadef H et al. Genet Test Mol Biomarkers 2009; 13(6): 855–859
11. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA.
Coffee B et al. Am J Hum Genet 2009; 85(4): 503–514
**The authors evaluated 36,124 deidentified newborn males using a quantitative methylation PCR assay on pooled sample blood spots. Out of 64 males with FMR1 methylation, seven FXS males had a full mutation FMR1 allele yielding an incidence in males of 1 in 5161 [95% CI: 1/2500-1/10653]. Given the trials now underway for possible FXS treatments, this method could be used in newborn or infant screening as a way of ensuring early interventions for FXS.
12. A model for offering carrier screening for fragile X syndrome to nonpregnant women: results from a pilot study.
Metcalfe S et al. Genet Med 2008; 10(7):525-535
13. High-risk fragile x screening in Guatemala: use of a new blood spot polymerase chain reaction technique.
Yuhas J et al. Genet Test Mol Biomarkers 2009; 13(6): 855–859
14. Principles and practice of mass screening for disease.
Wilson JM, Jungner YG. Bol Oficina Sanit Panam 1968;65:281-393
15. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population.
Fernandez-Carvajal I et al. J Mol Diagn 2009; 11(4): 324–329
16. When to tell and test for genetic carrier status: perspectives of adolescents and young adults from fragile X families.
Wehbe RM et al. Am J Med Genet A 2009;149A(6):1190-1199
17. A systematic review of population screening for fragile X syndrome.
Hill MK et al. Genet Med 2010; 12(7):396-410
18. Qualitative assessment of FMR1 (CGG)n triplet repeat status in normal, intermediate, premutation, full mutation, and mosaic carriers in both sexes: implications for fragile X syndrome carrier and newborn screening.
Hantash FM et al. Genet Med 2010; 12(3):162-173
19. It's something I need to consider": decisions about carrier screening for fragile X syndrome in a population of non-pregnant women.
Archibald AD et al. Am J Med Genet A 2009; 149A(12):2731-2738
20. 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 FM et al. Genet Med 2011; 13(1):39-45
21. Expanded carrier screening and the law of unintended consequences: from cystic fibrosis to fragile X.
Grody WW. Genet Med 2011; 13(12):996-997
22. Caregiver opinions about fragile X population screening.
Bailey DB et al. Genet Med 2012; 14(1): 115-121
*Despite advances in technology for fragile X testing and educational programs on early detection, the average age of diagnosis is still 3 years and many families have a second affected child prior to diagnosis of the first. Improved access to fragile X testing and screening may alleviate the diagnostic odyssey encountered by parents and facilitate earlier access to interventions. Caregivers are generally supportive of carrier and newborn screening.
23. Population screening in the age of genomic medicine
Khoury MJ, McCabe LL, McCabe ER. N Engl J Med 2003;348:50-8.
*The current and evolving principles of population screening in genetics are moving from “intense, crisis-driven intervention to predictive medicine.” Genetic information will increasingly be used in population screening to determine individual susceptibility to common disorders. While fragile X is not used as an example in this study, the key drivers of technology and access to informative information highlighted in other disease categories can influence broader screening for fragile X syndrome.