Fragile X syndrome is caused by CGG trinucleotide repeat expansion in the 5' UTR of FMR1. When the repeat number exceeds 200 (full mutation), which epigenetic change silences FMR1?

• A Promoter hypermethylation with gene silencing ✓
• B Histone acetylation
• C Loss of heterozygosity of FMR1
• D Frameshift mutation in exon 2

Explanation

When CGG repeats in FMR1 exceed ~200, the CpG islands in the FMR1 promoter region become hypermethylated, leading to transcriptional silencing and loss of FMRP (fragile X mental retardation protein), an RNA-binding protein critical for synaptic plasticity. Premutation carriers (55–200 repeats) express reduced FMRP and are at risk for fragile X-associated tremor/ataxia syndrome (FXTAS) and premature ovarian failure.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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