A 4-year-old boy has global developmental delay, large ears, a long face with a prominent jaw, macroorchidism noted on examination, and autistic behaviour. Family history reveals an affected maternal uncle. DNA testing shows more than 200 CGG repeats with methylation of the promoter in the FMR1 gene. What is the underlying mutational mechanism?

• A Deletion of exons in the FMR1 gene causing a frameshift
• B Point mutation creating a premature stop codon in the coding sequence
• C Expansion of a trinucleotide repeat beyond threshold with CpG methylation silencing transcription ✓
• D Uniparental disomy of chromosome X with imprinting abnormality

Explanation

Fragile X syndrome results from expansion of a CGG trinucleotide repeat in the 5' untranslated region of FMR1. Premutation carriers have 55 to 200 repeats; full mutation exceeds 200 repeats, triggering CpG methylation that silences transcription and abolishes FMRP production. Anticipation occurs through transmission by carrier mothers. Deletions and nonsense point mutations are rare alternative causes, and uniparental disomy plays no role in this disorder.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.