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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...

PurposeTo describe our experience of offering simultaneous genetic carrier screening for cystic fibrosis (CF), fragile X syndrome (FXS), and spinal muscular atrophy (SMA).MethodsCarrier screening is offered through general practice, obstetrics, fertility, and genetics settings before or in early pregnancy. Carriers are offered genetic counseling with prenatal/preimplantation genetic diagnosis available to those at increased risk.ResultsScreening of 12,000 individuals revealed 610 carriers (5.08%; 1 in 20): 342 CF, 35 FXS, 241 SMA (8 carriers of 2 conditions), approximately 88% of whom had no family history. At least 94% of CF and SMA carriers' partners were tested. Fifty couples (0.42%; 1 in 240) were at increased risk of having a child with one of the conditions (14 CF, 35 FXS, and 1 SMA) with 32 pregnant at the time of testing. Of these, 26 opted for prenatal diagnosis revealing 7 pregnancies affected (4 CF, 2 FXS, 1 SMA).ConclusionThe combined affected pregnancy rate is comparable to the population risk for Down syndrome, emphasizing the need to routinely offer carrier screening. The availability of appropriate genetic counseling support and a collaborative approach between laboratory teams, genetics services, health professionals offering screening, and support organizations is essential.

PURPOSE Fragile X syndrome (FXS) is one of several clinical disorders associated with mutations in the Xlinked 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 researchbased 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.

Reproductive genetic carrier screening aims to offer couples information about their chance of having children with certain autosomal recessive and X-linked genetic conditions. We developed a gene list for use in "Mackenzie's Mission", a research project in which 10,000 couples will undergo screening. Criteria for selecting genes were: the condition should be lifelimiting or disabling, with childhood onset, such that couples would be likely to take steps to avoid having an affected child; and/or be one for which early diagnosis and intervention would substantially change outcome. Strong evidence for genephenotype relationship was required. Candidate genes were identified from OMIM and via review of 23 commercial and published gene lists. Genes were reviewed by 16 clinical geneticists using a standard operating procedure, in a process overseen by a multidisciplinary committee which included clinical geneticists, genetic counselors, an ethicist, a parent of a child with a genetic condition and scientists from diagnostic and research backgrounds. 1300 genes met criteria. Genes associated with non-syndromic deafness and non-syndromic differences of sex development were not included. Our experience has highlighted that gene selection for a carrier screening panel needs to be a dynamic process with ongoing review and refinement.

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 Xassociated 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 nonpregnant 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 decisionmaking 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.

Advancing genetic testing technologies mean that population-based carrier screening for multiple inherited conditions is now available. As the number of genetic conditions being screened increases, there is a need for research into how people experience these screening programs. This research aimed to explore how women experience simultaneous carrier screening for three inherited conditions: cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS). A qualitative approach was adopted using in-depth semi-structured interviews to explore the experiences of ten female participants: five SMA carriers, three CF carriers, and two FXS premutation carriers. Eight participants were pregnant when offered screening by their general practitioner or obstetrician and the decision to have screening was described as straightforward. Participants reported experiencing emotional responses such as anxiety and stress while waiting for either their partner's carrier screen result (CF or SMA carriers) or the pregnancy's CVS result (FXS carrier) and sought additional information about the relevant condition during this time. Most participants were in favor of population carrier screening for these conditions, preferably prior to conception. Genetic counselors played an essential role in supporting couples after they received a carrier result given the variable consent processes undertaken when screening was offered. Further research should focus on the development of reliable online information tailored to people receiving carrier results and strategies for raising awareness of the availability of population carrier screening within the community. © 2016 Wiley Periodicals, Inc.

Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay‐Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X‐linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions. Different programs target different groups (high school, premarital, couples before conception, couples attending fertility clinics, and pregnant women) as does the governance structure (public health initiative and user pays). Ancestry‐based offers of screening are being replaced by expanded carrier screening panels with multiple genes that is independent of ancestry. This review describes screening in Australia, Cyprus, Israel, Italy, Malaysia, the Netherlands, Saudi Arabia, the United Kingdom, and the United States. It provides an insight into the enormous variability in how reproductive carrier screening is offered across the globe. This largely relates to geographical variation in carrier frequencies of genetic conditions and local health care, financial, cultural, and religious factors.