Genetic Counseling and Testing for FMR1 Gene Mutations

Publication Date: July 1, 2012
Last Updated: March 14, 2022

Recommendations

Counseling Considerations

Centers offering population screening should ensure that they have the resources available to provide pre‐ and post‐test genetic counseling that supports the psychosocial and clinical needs of the patient and family. In light of widespread FMR1 testing among women without known risk factors, genetic counselors should anticipate seeing patients who did not receive any pre‐test information, have no prior knowledge of FMR1‐associated disorders, and are unprepared to learn that they have an FMR1 mutation.
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Although many genetic counselors are familiar with FXS, fewer have experience with FXTAS and FXPOI. As such, they may underestimate the scope of clinical inquiry needed for risk assessment in families with FMR1 mutations. Taking a pedigree in these families requires attention to a diverse constellation of developmental, neurodegenerative, and reproductive symptoms that vary widely in age of onset and severity across multiple generations. Specific family history queries designed to identify individuals with the full spectrum of FMR1 gene mutations are listed in Table 7. Given the subjective nature of behavioral and cognitive symptoms, psychiatric and educational records should be obtained whenever possible to confirm a reported history of developmental issues.
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The diagnosis of FMR1‐associated disorders can have far‐reaching genetic and emotional implications for extended family members. When an FMR1 mutation is identified in a family, genetic counselors should assist patients in developing strategies to inform relatives.
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Parents should be encouraged to explore open and meaningful discussion with their children about FMR1‐associated disorders and genetic risk. Genetic counselors should work toward helping parents develop a positive, resilient communication style which may aid in the long‐term adaptation of children to FMR1‐related risk.
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Psychiatric issues, as well as cognitive decline, are common among patients with FXTAS. They may experience confusion and emotional reactions to learning the genetic nature of their condition and its implications for their children and other relatives. With the patient's consent, it may be important to involve other family members and caregivers in these discussions so that genetic and management information is accurately communicated.
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Patients who have normal laboratory results should be counseled that FMR1 testing does not rule out other genetic conditions or determine the cause of undiagnosed developmental disabilities, infertility, or neurodegenerative disorders in other family members.
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Intermediate Alleles

Conflicting research on the phenotypic and reproductive implications of intermediate alleles makes it difficult for genetic counselors to provide clear cut guidance to these patients. Counseling in these situations should include a discussion of known reproductive and clinical implications of intermediate alleles. In the absence of further data to the contrary, the focus should be on the low rate of instability and limited evidence to indicate increased risk for developing FMR1‐associated disorders.
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Patients with intermediate alleles who present with clinical signs suggestive of FMR1‐associated disorders should be counseled about the likely possibility of an unrelated etiology for their symptoms and referred, as indicated, for additional diagnostic work‐up.
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Intermediate alleles are common and often detected coincidentally as part of an infertility work‐up, through general population screening in women without a family history of FMR1 mutation disorders, or in children undergoing evaluation of developmental delay or autism. Genetic counselors should anticipate a heightened level of anxiety and reactions in these patients, particularly since many have had little or no pre‐test counseling to prepare them for the result.
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Prenatal diagnosis should be offered to women with pre‐ or full mutations. Males with premutation alleles should receive genetic counseling about potential phenotypic risks to their daughters, all of whom will inherit premutations.
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Genetic counselors should be alert to female family members who could be pursuing fertility treatments while unaware that they have an underlying FMR1 premutation and a risk for having children with FXS.
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Since a main determinant of successful PGD is ovarian function, women with FMR1 premutations should be evaluated for subfertility prior to consideration of PGD.
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At this time, there are no reports of intermediate alleles expanding to full mutations in a single generation, and invasive prenatal diagnosis is not medically indicated. Despite this, some patients with intermediate alleles, especially if they are already pursuing prenatal diagnosis for another indication, request fragile X prenatal testing to confirm that the fetus does not have a full mutation. Less frequently, patients may ask for prenatal testing to determine if an intermediate allele is unstable and has expanded into a premutation, based on concerns about potential phenotypic features, most of which would manifest in adulthood, if at all. In these circumstances, genetic counseling is crucial given the issues surrounding prenatal testing for adult onset disorders and the inability to predict the premutation phenotype.
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Treatment and Resources

In light of the rapid pace of drug development for FXS, genetic counselors need to be informed about current research on targeted pharmaceuticals. While these are still in the research phase, genetic counselors can facilitate the informational process and help families consider both positive and negative aspects of enrolling in a clinical research study.
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The National Fragile X Foundation (www.fragileX.org) provides extensive educational resources and support for families and professionals. The Foundation maintains a Facebook social networking site for families affected by fragile X‐associated disorders, as well as a separate informational site for individuals with FXTAS (www.fxtas.org).
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FRAXA Research Foundation (www.fraxa.org) raises funds to accelerate research progress toward effective treatments, and it also supports families and raises awareness about FXS.
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The Fragile X Clinical and Research Consortium (www.fxcrc.org) fosters the international development of fragile X specialty clinics and provides a structure for collaborative research efforts, including drug trials. Families should be encouraged to contact the consortium to locate their nearest FXCRC center about clinical management of FXS and other FMR1‐related disorders.
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Recommendation Grading

Disclaimer

Overview

Title

Genetic Counseling and Testing for FMR1 Gene Mutations

Authoring Organization

Publication Month/Year

July 1, 2012

Last Updated Month/Year

August 21, 2023

Supplemental Implementation Tools

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Document Objectives

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.

Target Patient Population

Patients with FMR1-associated disorders

Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory, Laboratory services, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Counseling, Assessment and screening, Diagnosis

Diseases/Conditions (MeSH)

D060825 - Cognitive Dysfunction, D005817 - Genetic Counseling, D005600 - Fragile X Syndrome, D051860 - Fragile X Mental Retardation Protein

Keywords

cognitive impairment, genetic counselors, genetic counseling, fragile x mental retardation