Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, is an X-linked genetic condition that exemplifies these issues. FXS is caused by a CGG trinucleotide repeat expansion (>200 repeats) of the FMR1 gene that, when methylated, causes the reduction or absence of a protein (FMRP) necessary for normal brain development and functioning. Absence of FMRP leads to the overactivation of mGluR5, a metabotropic glutamate receptor affecting synaptic plasticity.¹³ Males with FXS typically have moderate intellectual disability and a variety of co-occurring conditions, the most common being anxiety, inattention, hyperactivity, and autism or autistic symptoms.¹⁴ Intellectual functioning in females can range from typical cognitive abilities to moderate impairment, a spectrum largely due to X inactivation. It is estimated that ~1 per 4000 males and 1 per 6000 females have the full mutation.^15,16

The FMR1 full mutation leading to FXS is maternally inherited either from a carrier of a premutation (55–200 CGG repeats) or a full mutation. The prevalence of the premutation is common, estimated at 1 per 290 to 800 in males and 1 per 129 to 259 in females.^15,16 Female carriers have an elevated risk for primary ovarian insufficiency and early menopause¹⁷; males and, to a lesser extent females, have an increased risk for fragile X tremor ataxia syndrome, a debilitating neurologic impairment occurring after 50 years of age.¹⁸ Recent animal and human studies have demonstrated that some carriers may have other neurologic or emotional problems, suggesting a broader range of risk and disability than has been previously assumed.^14,19–22

The rationale for FXS NBS includes a persistently delayed age of diagnosis²³; the strong support by parents of affected children²⁴; and possible benefits for families such as prevention of the “diagnostic odyssey” and its financial and emotional costs; and the early availability of information about FXS, parents' reproductive risks, and appropriate services for the child's special needs.²⁵ After weighing these and other benefits, an American College of Medical Genetics task force did not recommend FXS for inclusion in state NBS,²⁶ however, primarily due to the lack of a cost-effective screening test and the absence of data on possible benefits from identification of newborns. DNA-based screening for a CGG expansion also identifies carriers, evoking a wide range of ethical, legal, and social concerns. Besides the current lack of a medical treatment for children identified with the full mutation, perhaps the most fundamental concern is triggered by the ambiguity of the risk for carriers to have developmental problems or adult-onset disorders such as fragile X tremor ataxia syndrome and primary ovarian insufficiency. Presymptomatic identification of children could lead to a range of adverse outcomes, such as elevated rates of postpartum depression, parents' ongoing anxiety and worry about their child's future, and possible disruptions to the parent-child relationship.^2,4,11,27

Most of these risks and benefits are not unique to FXS and apply to a wide range of other genetic conditions likely to be considered for inclusion on NBS panels. Determining whether these hypothesized risks and benefits are valid can only be accomplished by examining them in a prospective screening study. After careful deliberation of the ethical and social implications⁴ and based on our previous research with families of children with FXS,^24,28 we designed a research project at the University of North Carolina Hospitals that offers, through a voluntary consent process, NBS for FMR1 gene expansions. Our rationale for the study was that there are multiple concerns and speculations about the risks and benefits of expanded screening but very little empirical investigation. The study uses FXS as a prototype for studying issues such as public willingness to accept screening for conditions that are not medically treatable or those that would identify newborns as carriers and/or at risk for late-onset conditions, and how families adapt to genetic information and to their identified child.⁴

We initiated the pilot study in February 2009, once a cost-effective screening test was available.²⁹ The screening test identifies both the premutation and full mutation in males and females. The study's long-term aim was to follow-up identified and matched comparison families to assess family adaptation and child development. In this article, we report findings on rates of parental consent, examine demographic characteristics of parents who consented or declined, describe the reasons parents gave for their decisions, and discuss ethical and social aspects of the consent process. For the sake of brevity and clarity, we use the term fragile X (FX) to include both carriers (CGG repeat length of 55–200) and individuals with fragile X syndrome (FXS) (CGG repeat length >200).

In a previous article, we examined possible challenges to an informed consent process in screening for FX in the neonatal setting.⁴ These challenges included the ability to adequately explain the potential consequences of having FXS or of being a premutation carrier, and the possible ramifications of a positive diagnosis for the family, including confirmatory testing and genetic counseling. Although we designed educational and consent materials to convey this information, and RAs were trained to explain and discuss the study and FX in more detail, the reasons some parents gave, or did not give, indicate that they may not have fully understood the study or FX and its personal, familial, and social consequences. For example, the mother who indicated she consented to the screening to help to find cures for diseases may have misunderstood the purpose of the study. Parents who gave as a reason for consenting “to help my child get better” may have not understood that there is no cure or standard medical treatment or they may have been referring to early-intervention services. Those who declined the study because the infant looked healthy or there were no problems in their family may not have understood how FX is inherited or manifests, but they may also have not wanted to consider that something could be wrong with their newborn. The lack of responses about a positive result providing information on reproductive risk or possible medical conditions in adult carriers is likely due to parents at this time focusing more on the implications of a positive diagnosis for the newborn and not what this information would mean for others. About one fourth of those who declined also indicated that the timing and context of consent were not optimal, raising the issue of the most appropriate time for consent and screening. Parents' opinions about these issues warrant additional study. We are currently conducting interviews with a subset of decliners and negatively screened acceptors to examine in more detail their evaluations of the consent process, understanding of the information presented, and reasons for their decision. We are also assessing the positive screened families to ascertain their responses and experiences related to the diagnosis.

For the most part, the reasons given by the vast majority of parents for accepting or declining suggest that they were assessing many of the risks and benefits of the study and were making decisions based on what they most valued, or perhaps most feared. Although acceptance rates were lower than other NBS pilot studies, almost two thirds of families consented, indicating more parental support for testing for FMR1 gene expansions in the newborn period than reported among pediatricians or genetic counselors.^37,38 This is consistent with studies that indicate parents may view the benefits of expanded screening more broadly than defined by current criteria for NBS and are supportive of such screening with informed consent.³⁹ Our findings also indicate some difference in acceptance rates according to race/ethnicity, with black respondents somewhat less likely to consent to screening. This may be due to mistrust rising from the historical legacy of medical and genetic research in the United States with blacks^40–42 or to a different valuing of the benefits and risks of screening. We cannot answer this question from our data but acknowledge that the role of race/ethnicity versus cultural differences in medical decision making is complex and requires additional investigation.