Clinical Scenario:
A 3-year-old boy is evaluated for developmental delay. He has a long face, large ears, joint hypermobility, and mild macrocephaly. His mother reports that her brother has significant intellectual disability. Genetic testing identifies an expansion of the CGG trinucleotide repeat in the FMR1 gene. The number of repeats is substantially larger in the affected child than in his maternal uncle.
Which of the following best explains this pattern?
A. Autosomal dominant inheritance with variable penetrance
B. Genomic imprinting
C. Mitochondrial heteroplasmy
D. Mosaic trisomy
E. Trinucleotide repeat expansion with anticipation
Correct answer & Explanation:
Answer: E. Trinucleotide repeat expansion with anticipation
Explanation
This is Fragile X syndrome, caused by expansion of a CGG trinucleotide repeat in the FMR1 gene on the X chromosome.
The number of CGG repeats can increase during transmission, particularly when a premutation is transmitted by a woman. Expansion to a full mutation leads to methylation and silencing of the FMR1 gene, resulting in Fragile X syndrome.
This phenomenon is known as anticipation, in which the disorder may become more severe or present earlier in successive generations as the repeat expands.
The family history is also characteristic: an affected boy may have an affected maternal uncle because the mutation is transmitted through the maternal line.
Exam pearl:
Fragile X → FMR1 → CGG expansion → anticipation → maternal transmission is associated with expansion to a full mutation.
