Testing Recommendations for Fragile X Syndrome
For a patient with confirmed fragile X syndrome, comprehensive medical surveillance and family cascade testing are essential, rather than additional diagnostic genetic testing for the patient themselves.
Initial Evaluation of the Diagnosed Patient
Once fragile X syndrome is confirmed, the focus shifts from diagnosis to comprehensive medical assessment and management:
Complete physical examination should assess for characteristic features including macroorchidism (in males), long face, prominent ears, joint hypermobility, and cardiac abnormalities (particularly mitral valve prolapse) 1
Baseline cardiac evaluation with echocardiography is recommended to screen for mitral valve prolapse and aortic root dilation, which occur in approximately 50-80% of males with fragile X syndrome 1
Ophthalmologic examination should be performed to evaluate for strabismus and refractive errors, which are common in fragile X syndrome 1
Audiologic assessment is necessary as recurrent otitis media and hearing difficulties are frequent complications 1
Developmental and cognitive assessment using standardized tools should establish baseline functioning and guide educational interventions 1
Behavioral and psychiatric evaluation should screen for ADHD, anxiety disorders, autism spectrum features, and other psychiatric comorbidities that occur in the majority of individuals with fragile X syndrome 1
Family Cascade Testing (Critical Priority)
The most important "testing" after a fragile X diagnosis is systematic evaluation of at-risk family members, as this has profound reproductive and medical implications:
All first-degree female relatives (mother, sisters, daughters) should be offered FMR1 testing, as they may be premutation or full mutation carriers 1
Maternal lineage screening should extend to aunts, female cousins, and other maternal relatives, as fragile X follows X-linked inheritance with anticipation 1
Male relatives through maternal lineage should be tested, as they may carry premutations putting them at risk for fragile X-associated tremor/ataxia syndrome (FXTAS) later in life 1
Premutation carrier females require counseling about 20% risk of fragile X-associated primary ovarian insufficiency (FXPOI) and increased FXTAS risk with aging 1
Older male premutation carriers (typically >50 years) should be monitored for FXTAS symptoms including intention tremor, ataxia, cognitive decline, and neuropathy 1
Metabolic and Specialty Testing (When Clinically Indicated)
While not routine, certain tests may be warranted based on clinical presentation:
Thyroid function tests should be considered as hypothyroidism occurs with increased frequency in fragile X syndrome 2
Metabolic screening is only indicated if there are specific clinical features suggesting an additional metabolic disorder (developmental regression, episodic decompensation, hepatosplenomegaly) 1
Electroencephalogram (EEG) should be performed if seizures are suspected, as approximately 10-20% of individuals with fragile X syndrome develop epilepsy 1
Brain MRI is not routinely recommended unless there are focal neurologic findings, significant microcephaly or macrocephaly, or atypical features suggesting an alternative or additional diagnosis 1
Additional Genetic Testing Considerations
Chromosomal microarray analysis should be considered if the clinical presentation includes features not typical of fragile X syndrome alone, as approximately 10% of individuals may have additional pathogenic copy number variants 1
Exome or genome sequencing is not routinely indicated for typical fragile X syndrome but may be considered if there are atypical features, severe congenital anomalies, or lack of expected phenotype-genotype correlation 1
MECP2 testing should be considered in females with fragile X who have severe intellectual disability and features suggestive of Rett syndrome, as dual diagnoses can occur 1
Common Pitfalls to Avoid
Do not assume all family members are aware of their risk - systematic cascade testing often identifies previously unknown carriers who need reproductive counseling 1, 3
Do not use methylation status or X-inactivation patterns to predict phenotype severity in females with full mutations, as correlation is poor 1
Do not dismiss premutation carriers as "unaffected" - they require counseling about FXTAS and FXPOI risks, which have significant medical implications 1
Do not order fragile X testing repeatedly on the same patient - the diagnosis is definitive and the mutation does not change over time 1
Do not overlook the need for genetic counseling for all family members, as reproductive implications and cascade testing are complex 1, 3