Re-evaluating the first-tier status of fragile X testing in neurodevelopmental disorders

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Diagnostics

Background:

• Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism spectrum disorder.
• Current diagnostic guidelines for FXS testing vary, particularly in cases without a clear family history or suggestive clinical presentation.
• Evaluating the diagnostic yield of FXS testing is crucial for optimizing resource allocation and clinical practice.

Purpose of the Study:

• To assess the diagnostic yield of fragile X syndrome (FXS) testing in pediatric patients with neurodevelopmental disorders.
• To determine the proportion of FXS-positive cases that present with suggestive clinical features or a family history.
• To evaluate the potential for transitioning FXS testing to a second-tier diagnostic approach.

Main Methods:

• Retrospective chart review of 2486 pediatric patients tested for FXS at Alberta Children's Hospital (ACH) between 2012 and 2017.
• Analysis of FXS diagnostic yield based on patient demographics and testing results.
• Detailed review of FXS-positive cases to identify the presence or absence of suggestive clinical features and family history.

Main Results:

• A total of 30 patients (25 males, 5 females) tested positive for FXS, yielding a diagnostic rate of 1.2%.
• Of the FXS-positive individuals, 96% exhibited clinical features and/or a family history suggestive of the syndrome.
• Only one patient lacked both suggestive clinical features and a family history, indicating strong clinical correlation in most positive diagnoses.

Conclusions:

• FXS testing demonstrates a high correlation with clinical suspicion based on features and family history, with 96% of positive cases meeting these criteria.
• The findings support the proposal to transition FXS testing to a second-tier diagnostic test for neurodevelopmental disorders when clinical suspicion is absent.
• This strategic shift can help optimize diagnostic pathways and resource utilization for intellectual disability and autism spectrum disorder evaluations.