EP341: The full (mutation) picture: One-third of patients with Fragile X syndrome present with neurodevelopmental disorders without dysmorphism or family history

Abstract

Fragile X syndrome (FXS) has long been described as the most common single gene cause of intellectual disability (ID). In >99% of cases, the diagnosis is secondary to an FMR1 full mutation (FM; >200 CGG repeats) resulting in aberrant promoter hypermethylation and loss of FMRP production. Guidelines from the ACMG and AAP support FMR1 analysis as a first-tier test for individuals with neurodevelopmental disorders (NDDs) including ID, developmental delay (DD), and autism spectrum disorder (ASD). Since the establishment of these guidelines in 2005 and 2011, respectively, several groups have called into question the utility of first-tier testing for FXS, citing a low diagnostic yield and frequent presence of suggestive clinical features in affected individuals (dysmorphism and/or family history).