A systematic review of population screening for fragile X syndrome

Abstract

Purpose: To conduct a systematic review of literature regarding population-based screening for fragile X syndrome in newborns and women of reproductive age, either before or during pregnancy. Methods: Seven electronic databases were searched for English language studies published between January 1991 and November 2009. Data extraction was performed for all included studies. Results were synthesized using a narrative approach. Results: One article that examined offering newborn screening for fragile X syndrome and 10 that examined the offer of fragile X syndrome screening to women of reproductive age were identified. Two of these articles also addressed psychosocial aspects of population screening for fragile X syndrome such as attitudes to screening and experiences of screening, and a further nine addressed these issues alone. Studies exploring psychosocial issues demonstrated challenges for counseling arising from a lack of awareness or personal experience with fragile X syndrome in the general population. Conclusions: Targeted counseling and educational strategies will be essential to support women from the general population. It is crucial that future studies offering screening for fragile X syndrome explore a range of psychosocial aspects in addition to looking at uptake of testing and mutation frequency. Genet Med 2010:12(7):396 -410.Key Words: attitudes, carrier screening, fragile X syndrome, newborn screening, psychosocial P opulation-based screening programs for a number of genetic conditions have been established in newborn, prenatal, and preconception settings. Specific criteria, such as those developed by the World Health Organization, 1,2 are available to provide guidance on which conditions are suitable for screening. 3 Fragile X syndrome (FXS) is an X-linked genetic condition for which possible inclusion in population-based screening programs has been discussed and debated for many years. 4 -7 FXS is the most common known cause of inherited intellectual and developmental disability. It has a serious adverse impact on individuals and their families that is equivalent to that of other disabilities such as Down syndrome and autism. Most FXS cases are caused by the silencing of the FMR1 gene, which is located on the X chromosome. In these cases, the FMR1 gene is switched off as a result of an increase in the number of hypermethylated trinucleotide (CGG) repeats in the 5Ј untranslated region of the gene. Current definitions describe the normal range of CGG repeats as 6 -44, the "gray zone" range as 45-54 repeats, and the premutation range as 55-199 repeats. 8 Those affected by FXS have Ͼ200 repeats (full mutation). The length of the CGG repeat is unstable over a certain size, such that a premutation can expand to a full mutation when passed onto offspring through female, but not male, premutation carriers. 9 -11 Similarly, a gray zone allele can increase to a premutation allele when transmitted to offspring, such that a grandchild could be affected with FXS.The full mutation is associated with intell...

A mixed methods exploration of families’ experiences of the diagnosis of childhood spinal muscular atrophy

“…25 There is much discussion about possible expansion and evaluation of NBS programs to include other conditions such as DMD [25][26][27] and FXS. [28][29][30] Similarly, SMA could be considered for inclusion. 7 When presented with screening options, such as screening children in the newborn or infant period, participants in our study highlighted the complexity of choosing an appropriate time to test, because of the variability in the phenotype between SMA types and even within the same SMA type.…”

Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study

“…7 The psychosocial consequences of preconceptional CGG repeat length screening have been studied in great detail and were found to be in favor of a generalized screening. [8][9][10] In addition, the attitudes of key medical care stakeholders toward the challenges of general population-based screening programs were found to be favorable, 6,11 and preconceptional testing was most endorsed. 12 Despite these well-studied advantages of a population-based screening and the wide acceptance among key stakeholders of medical care, screening programs have so far only been conducted in research settings.…”

“It gives them more options”: preferences for preconception genetic carrier screening for fragile X syndrome in primary healthcare

“…Although funding for genetic carrier screening varies internationally, for tests in which the consumer bears the cost of the screening, genetic counseling resources should be factored into the screening fee so that genetic counseling support is accessible to those considering and undergoing screening as well as those who receive carrier results. While much research has shown that FXS carrier screening is feasible (Hill et al 2010), limited awareness of FXS and of the availability and implications of genetic screening was identified as a major issue which may impact the utilization of a screening program. This concern is not unique to FXS and is a potential barrier to the delivery of genetic carrier screening services.…”

“…As such, FXS carrier screening, either stand-alone or as part of expanded screening, provides a useful model through which to consider carrier screening approaches because of the complexity and duality of risk information provided (Henneman et al 2016). As outlined by Hill et al (2010), arguments for carrier screening for FXS include a high prevalence (which may be up to 1 in 2500 in males and females (Hagerman 2008)) and high carrier frequency (recently reported to be 1 in 179 estimated for North American populations (Hantash et al 2011)), the prevalence of premutation alleles estimated as 1:209 in females and 1:430 in males (Tassone et al 2012), and an accurate testing method amenable to screening populations (Tassone et al 2008) which identifies an expanded CGG repeat in the FMR1 gene (the cause of FXS in over 99 % of cases). In addition, the condition is well understood and defined; there are a range of significant phenotypic effects associated with the full mutation (FM ≥200 hypermethylated CGG repeats) including intellectual disability and cognitive, behavioral, and medical problems, which have a substantial impact on the affected individual and their family (Hagerman and Hagerman 2002).…”

“…Despite research indicating that there is support for population carrier screening for FXS (Hill et al 2010), the American College of Medical Genetics only recommends screening as part of clinical research protocols . Recommendations from the American College of Obstetricians and Gynecologists (2010) suggest that carrier screening be offered to women without a family history of FXS if it is requested.…”