A 6-year-old boy presents with global developmental delay, autistic features (poor eye contact, hand-flapping), and hyperactivity. On examination, he has a long narrow face, prominent forehead, large protuberant ears, and hyperextensible joints. His maternal uncle has fragile X-associated tremor/ataxia syndrome. Karyotype shows 46,XY with a folate-sensitive fragile site. Southern blot confirms a full mutation at the structure marked **A** in the diagram. Which of the following best describes the molecular consequence of this mutation?
A. Trinucleotide repeat expansion causing direct loss of HTT protein function and neuronal degeneration
B. CTG repeat expansion in the 3' UTR leading to RNA toxicity and myotonic dystrophy phenotype
C. Hypermethylation of the FMR1 promoter leading to transcriptional silencing and loss of FMRP, an RNA-binding protein regulating synaptic protein translation
D. GAA repeat expansion in the first intron causing frataxin deficiency and spinocerebellar degeneration
Explanation
Why option 1 is correct
The structure marked A represents Xq27.3 with a full FMR1 CGG expansion (>200 repeats). In Fragile X Syndrome, this expansion triggers hypermethylation of the FMR1 promoter, silencing transcription and eliminating FMRP production. FMRP is an RNA-binding protein essential for regulating synaptic protein translation at dendrites via the mGluR5 pathway. Loss of FMRP causes exaggerated metabotropic glutamate signaling and aberrant long-term depression, explaining the intellectual disability, autism spectrum behaviors, and ADHD observed in this patient. This is the pathognomonic mechanism of Fragile X Syndrome (Nelson Textbook of Pediatrics 22e, Ch 54; Hagerman GeneReviews 2023).
Why each distractor is wrong
Option 2: HTT CAG expansion occurs on chromosome 4 and causes Huntington disease, not Fragile X Syndrome. While both are trinucleotide repeats, the chromosome location, repeat type, and clinical phenotype are entirely different. This patient's karyotype shows the fragile site at Xq27.3, not chromosome 4.
Option 3: DMPK CTG expansion on chromosome 19 causes myotonic dystrophy, characterized by myotonia, muscle weakness, and cardiac conduction defects—not the developmental delay and autism seen here. The anchor is Xq27.3, not chromosome 19.
Option 4: FXN GAA expansion on chromosome 9 causes Friedreich ataxia, presenting with progressive ataxia, cardiomyopathy, and diabetes—a completely different phenotype. The location (chromosome 9) and clinical features do not match this patient's presentation or the marked structure A.
High-YieldNEET PG
Fragile X Syndrome is the most common inherited cause of intellectual disability and the leading monogenic cause of autism; diagnosis requires Southern blot or PCR-based CGG repeat sizing plus methylation analysis to confirm the full mutation (>200 repeats) and hypermethylation silencing at Xq27.3.
Nelson Textbook of Pediatrics 22e Ch 54; Hagerman GeneReviews Fragile X 2023
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