Fragile X syndrome — formative SAQs

SAQ 1 (10 marks)

A three-year-old boy is referred for global developmental delay and "autistic features". He walked at 20 months and has fewer than ten single words. His mother's brother has intellectual disability and lives in supported accommodation. A previous paediatrician sent a chromosomal microarray, which returned normal. The parents ask why you are ordering more tests. [1] [5]

a) Explain why a normal chromosomal microarray does not exclude fragile X syndrome, and name the specific two-part molecular test you will order. (3 marks) [1] [5]

b) Define the four FMR1 CGG-repeat allele classes, giving the repeat boundaries and methylation status of each. (3 marks) [3] [5]

c) Outline the comorbidity-driven management plan for this child, naming four domains beyond the genetic result that require active surveillance and support. (2 marks) [1]

d) Describe the cascade-testing obligation to the wider family, including the premutation-associated conditions you would screen for in his mother. (2 marks) [1] [9]

SAQ 2 (10 marks)

A 14-year-old girl is investigated for learning difficulty, anxiety, and selective mutism. She has a maternal family history of intellectual disability in males. Fragile X testing returns a methylated full mutation. Her mother is found to carry a premutation of 110 CGG repeats. [1] [9]

a) Explain why this girl is more mildly affected than a typical affected male, naming the molecular mechanism. (2 marks) [3]

b) Outline the reproductive counselling for the mother, explaining the maternal-expansion rule and the risk it confers on future pregnancies. (3 marks) [1] [9]

c) Describe the two premutation-associated conditions the mother herself is at risk of, and the surveillance that should follow. (3 marks) [9]

d) Discuss how you would coordinate care between the genetics service, the school, and the general practitioner to prevent loss of support at transition. (2 marks) [1]

Marking guide

SAQ 1. Chromosomal microarray detects copy-number variants across the genome but does not detect the FMR1 CGG-repeat expansion, so a normal microarray has not excluded fragile X. Order FMR1 PCR (to measure repeat number and detect premutation) plus methylation-sensitive PCR or Southern blot (to confirm full-mutation sizing and methylation status). The four allele classes are: normal (5 to 44, unmethylated, stable), intermediate (45 to 54, unmethylated), premutation (55 to 200, unmethylated, unstable with expansion risk), and full mutation (over 200, methylated, FMRP absent). Management is comorbidity-driven: developmental and educational support (early intervention, speech, OT, individualised education plan), autism assessment (M-CHAT then ADOS), seizure surveillance, and behavioural and mental-health support. Cascade testing of the mother, siblings, and at-risk relatives is obligatory, and the mother should be screened for fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). [1] [3] [5] [9]

SAQ 2. The girl is more mildly affected because of X-inactivation mosaicism: some of her cells inactivate the mutated X and express the normal allele, producing partial FMRP. The maternal-expansion rule states that a premutation of about 90 repeats or more has a very high risk of expanding to a full mutation in offspring, so a 110-repeat premutation confers a high full-mutation risk in each pregnancy, with a 50 percent chance of transmission per child. The two premutation-associated conditions are FXTAS (adult-onset intention tremor, ataxia, parkinsonism, cognitive decline) and FXPOI (premature ovarian insufficiency with subfertility and early menopause), warranting baseline neurological and ovarian-hormone surveillance. Coordination requires a written, shared care plan reconciled at every visit, with the school informed of the diagnosis and the educational plan, and a clear transition pathway to adult genetics and mental-health services. [1] [3] [9]