Genetic testing in a family shows a 10-year-old male with intellectual disability, macroorchidism, and elongated facies has 300 CGG repeats in the FMR1 gene. His mother has 90 CGG repeats. Why does the mother remain phenotypically unaffected despite carrying the mutation?

• A X-inactivation silences the expanded allele in most cells
• B Female carriers are always protected by the second X chromosome
• C The repeat expansion undergoes contraction in female germ cells
• D 90 repeats is a premutation; full mutation requires >200 repeats with FMRP silencing ✓

Explanation

Fragile X syndrome exhibits anticipation due to instability of CGG repeat expansion in the FMR1 gene. A premutation (55–200 repeats) causes no intellectual disability but carriers can develop FXTAS (Fragile X-associated tremor/ataxia syndrome) in later life (premutation-associated disorder due to toxic RNA gain-of-function). Full mutation (>200 repeats, typically 200–2000) leads to hypermethylation of the FMR1 promoter, silencing of FMRP protein production, and Fragile X syndrome. The premutation can expand to a full mutation during maternal (not paternal) meiosis. The mother with 90 repeats has a premutation and remains cognitively normal but is at risk for FXPOI (premature ovarian insufficiency).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.