USMLE® Step 1 Question of the Day: Fragile X syndrome
Published on Jan 3, 2024. Updated on Dec 15, 2023.
A 6-year-old adopted boy is brought to the physician to discuss his genetic testing results. The child had been having difficulties communicating with others in the classroom and was subsequently diagnosed with autism spectrum disorder and an intellectual disability. The genetic testing confirms a diagnosis of Fragile X syndrome. Which of the following family pedigrees represents this patient’s biological family history? (Arrows indicating the patient).
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The correct answer to today's USMLE® Step 1 Question is...
A.Before we get to the Main Explanation, let's look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!
Incorrect answer explanations
This family pedigree represents an X-linked recessive disorder, given that the males in the tree express the disease, and females are carriers. Fragile X syndrome is X-linked dominant.
C.Incorrect: In this pedigree, each female transmits the mutation to all of her children (males and females), while males do not transmit the disease to their offspring. This pattern occurs in mitochondrial disorders. Fragile X syndrome is instead inherited with an X-linked dominant pattern.
Incorrect: In this pedigree, males and females express the disease equally, and it does not skip generations–reflective of an autosomal dominant pattern. Fragile X Syndrome is an X-linked dominant disorder, and males cannot transmit the disease to their male offspring (i.e. no male-to-male transmission).
Incorrect: This pattern reveals skipping of generations, and the condition affects both males and females almost equally. This pattern is characteristic of autosomal recessive disorders. Fragile X syndrome is instead inherited with an X-linked dominant pattern.
This adopted child is found to have Fragile X syndrome, which is an X-linked dominant disorder that results from the trinucleotide repeat expansion of cytosine-guanine-guanine (CGG) on the X chromosome, which silences the Fragile X Mental Retardation 1 gene (FMR1).
X-linked dominant disorders refer to genetic mutations on the X-chromosome where only one copy of the mutated gene in the cell is sufficient to cause disease. Transmission of X-linked dominant disorders depends on which of the parents carry the mutated gene. If the father is affected (i.e. his only X chromosome has the mutation), then all of his female children will be affected by the disease. However, because the father gives away the Y chromosome for his male children, X-linked disorders cannot be transmitted from the father to his male children.
On the other hand, if the mother has an X-linked dominant disorder, there is a 50% chance that the mutated X chromosome will be transmitted to her offspring and a 50% chance of transmitting the normal copy of the X chromosome. Therefore, all of her children (males and females) have a 50% chance of having the disease.
In addition, it is important to note that trinucleotide repeat expansion disorders such as FGS exhibit anticipation – meaning with subsequent generations, the number of repeats will increase, so the symptoms of FGS will grow more pronounced as the mutation is passed down through generations.
Fragile X Syndrome is an X-linked dominant disorder. Children (males and females) of a mother with an X-linked dominant disorder have a 50% chance of having the mutant X chromosome. Fathers with X-linked dominant disorders transmit the disease to all their daughters, while the condition is never transmitted to their male children.
Stone WL, Basit H, Los E. Fragile X Syndrome. [Updated 2020 May 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459243/
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