Overlapping Pathways: Autism Spectrum Disorder in Fragile X Carrier States and the Need for Greater Awareness

Fragile X syndrome (FXS), caused by a full mutation (>200 CGG repeats) in the gene Fragile X messenger ribonucleoprotein 1 (FMR1), is the most common single-gene cause of autism spectrum disorder (ASD). Far less is known about the clinical significance of smaller FMR1 expansions. In this case series, we describe four male patients with ASD who carried the FMR1 intermediate (gray-zone) alleles (45-50 CGG; counts: 45, 49, 49, 50). All had early speech/language delay with ASD-consistent features (social-communication deficits, sensory sensitivities, and repetitive behaviors). Common comorbidities included attention-deficit/hyperactivity disorder (ADHD) features and sleep disturbance responsive to standard interventions. None of them met premutation (55-200 CGG) or full-mutation criteria. These observations align with emerging evidence that gray-zone alleles can be associated with neurodevelopmental phenotypes, including ASD traits, in a subset of carriers. Clinically, the series reinforces guidance to include FMR1 analysis in genetic evaluations for unexplained developmental delay/ASD and to provide counseling when intermediate results are identified. Awareness of a potential overlap between the FMR1 gray-zone states and ASD may aid comprehensive evaluation and family counseling. Larger, controlled studies, especially those incorporating AGG interruption analysis, are needed to quantify risk and clarify mechanisms underlying phenotypic variability.