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

Abstract

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.

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

“…Participants were unanimous in their views that individuals with test-positive results arising from FXS carrier screening should be provided with genetic counseling which is consistent with current recommendations (Finucane et al 2012;McConkie-Rosell et al 2007). Research indicates that individuals identified as carriers through population screening may differ in their genetic counseling needs compared with individuals who have a personal or family history of FXS, as they may be relatively unprepared for a carrier result (Anido et al 2005(Anido et al , 2007 and may have very limited knowledge and prior experience of FXS (Archibald et al 2009).…”

“…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. The need for appropriate education and genetic counseling has been emphasized as has the importance of research exploring psychosocial impacts of such screening (Finucane et al 2012;Sherman et al 2005). Research indicates that population screening for FXS is generally perceived favorably by families and healthcare providers (Acharya and Ross 2009;Archibald et al 2013;Ryynanen et al 1999;Skinner et al 2003) as well as individuals offered screening in research contexts (Anido et al 2005(Anido et al , 2007Archibald et al 2009;Fanos et al 2006;Metcalfe et al 2008;Sherman et al 2005), and there appears to be a preference for screening offered before pregnancy (Acharya and Ross 2009;Archibald et al 2013;Skinner et al 2003).…”

Ethical and Policy Issues in Newborn Screening of Children for Neurologic and Developmental Disorders

“…Emotional and psychiatric problems are common, even among those with normal intelligence. 43 Premutation carriers are at risk for 2 late-onset health conditions, fragile X-associated tremor/ataxia syndrome and fragile X premature ovarian insufficiency. Fragile X-associated tremor/ataxia syndrome is characterized by intention tremor, cerebellar ataxia, atypical parkinsonism, and dementia.…”

Commentary

“…This case demonstrates the importance of considering molecular genetic evaluation of FMR1 in the workup for secondary amenorrhea (1 ). Full mutations of FMR1 represent the most common inherited form of cognitive impairment, and premutations of FMR1 represent the most common inherited cause of POI.…”