Fragile X syndrome

Onset typically occurs in infancy or early childhood. Delayed attainment of motor and speech milestones is apparent in the first years of life. Affected males show intellectual disability with a mean IQ of 40-45 (range from less than 10 to within the normal range). Common early medical issues include hypotonia, gastro-oesophageal reflux, joint laxity, pes planus, recurrent otitis media, strabismus, sleep disorders, and seizures. Excessive softness and smoothness of the skin and a head circumference above the 50th percentile are also frequently observed. Craniofacial features (long face, prominent forehead, large ears, prominent jaw) and macroorchidism become more obvious with age and after puberty, respectively. Autism spectrum disorder is present in 50-70% of affected individuals and tends to be associated with more severe behavioural difficulties and a higher seizure rate. Females show the clinical features with lower frequency and milder severity than males, reflecting variable expressivity.

The estimated frequency of a full mutation in FMR1 is approximately 14:100,000 in males.

Fragile X syndrome is caused by a germline CGG repeat expansion in FMR1 (Xq27.3). When the expansion in the 5’ UTR of FMR1 exceeds 200 repeats (the full mutation), aberrant hypermethylation of the FMR1 promoter transcriptionally silences the gene, resulting in absence or deficiency of the FMR1 protein (FMRP). FMRP is an RNA-binding protein involved in neuronal synaptic plasticity, and its loss disrupts neurotransmission and underlies the neurodevelopmental phenotype.

Fragile X syndrome is an X-linked disorder caused by unstable CGG-repeat expansion in FMR1. Each child of a woman carrying a full mutation has a 50% chance of inheriting the expanded FMR1 allele; sons inheriting the expanded allele are typically more severely affected than daughters. Prenatal molecular testing is technically possible. Anticipation may be observed; premutation alleles transmitted maternally can expand into the full mutation in the next generation, increasing the number of affected individuals in successive generations.

Fragile X syndrome is diagnosed primarily by molecular genetic testing. Clinical suspicion arises from the combination of developmental delay or intellectual disability, autism spectrum disorder, and characteristic craniofacial findings, prompting targeted analysis of FMR1.

Main differential diagnoses include:

• : autistic-like behaviour without the cognitive and physical features of FXS; multiple genes.
• Fragile XE syndrome (FRAXE): milder intellectual disability and absence of the physical features of FXS; AFF2 (FMR2).
• : intellectual disability, behavioural problems, and seizures with overgrowth, characteristic facial appearance, and congenital cardiac, renal, or skeletal anomalies; NSD1.

• Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for genetic counselling and informed family planning.
• A confirmed molecular diagnosis enables specific and individualised surveillance and clinical management; molecular confirmation is the prerequisite for targeted medical care, which is decided by the treating physicians in consultation with the affected individual.
• Identification of an FMR1 repeat expansion enables predictive testing of at-risk relatives and informs reproductive planning.

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• Savatt JM, Myers SM. Genetic testing in neurodevelopmental disorders. Front Pediatr. 2021;9:526779. doi:10.3389/fped.2021.526779. PMID:; PMCID: PMC7933797.