Fragile X syndrome — MRCPsych Paper A MCQ

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EasyGeneticsFragile X syndromeMRCPsych Paper A

A 15-year-old boy has intellectual disability, prominent ears, post-pubertal macro-orchidism and marked anxiety. His mother has mild learning difficulties. Which genetic mechanism best explains this presentation and family pattern?

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Correct answer: C — X-linked inheritance due to a CGG repeat expansion

Explanation lettering: D = shown as A · A = shown as B · B = shown as D

C is correct. Fragile X syndrome is usually caused by expansion of a CGG trinucleotide repeat in the 5′ untranslated region of FMR1 on the X chromosome. A full mutation, usually exceeding 200 repeats, leads to methylation and silencing of FMR1. Intellectual disability, prominent ears, post-pubertal macro-orchidism and anxiety are characteristic in affected males. Mild learning difficulties in the mother are compatible with the variable phenotype seen in females carrying an FMR1 full mutation, partly because of X-chromosome inactivation. Autosomal deletion or point-variant mechanisms do not fit fragile X syndrome. Paternal uniparental disomy suggests an imprinting disorder rather than this phenotype, while mitochondrial inheritance neither explains the characteristic features nor the FMR1 repeat mechanism.

Reference: Royal College of Psychiatrists. CR237: The role of genetic testing in mental health settings, section 1, Genetic testing technologies, 2023. https://www.rcpsych.ac.uk/docs/default-source/improving-care/better-mh-policy/college-reports/College-report-CR237---Genetic-testing-in-mental-health-settings.pdf