A 3-year-old boy with Down syndrome is referred for genetic counseling. Karyotyping reveals the pattern shown as **B** in the diagram — a mixture of cells with normal chromosome complement (46,XY) and cells with trisomy 21 (47,XY,+21). The child has mild hypotonia, characteristic facial features, and an IQ in the low-normal range. His parents' karyotypes are normal. Which of the following best explains the mechanism of the condition marked **B** and the recurrence risk in future pregnancies?
A. Trisomy rescue followed by uniparental disomy; recurrence risk determined by parent-of-origin of retained chromosome
B. Meiotic non-disjunction in maternal meiosis II; recurrence risk approximately 1% plus maternal age-related background
C. Robertsonian translocation in one parent; recurrence risk 10-15% if mother is carrier
D. Mitotic non-disjunction in early post-zygotic cell divisions; recurrence risk essentially population risk plus maternal age-related background
Explanation
Why option 1 is correct
Mosaic Down syndrome (the condition marked B) arises most commonly from mitotic non-disjunction occurring in early post-zygotic cell divisions after fertilization, producing two genetically distinct cell lines (46,XY and 47,XY,+21) from a single zygote. Since the mosaicism is de novo (parents have normal karyotypes), the recurrence risk is very low — essentially the population risk plus the maternal age-related background risk for free trisomy 21, which is approximately 1%. This is substantially lower than the ~1% baseline recurrence risk for free trisomy 21 because the trisomic cell line did not originate from a parental meiotic error. The milder phenotype (lower hypotonia, higher IQ, fewer anomalies) in this child is consistent with a lower proportion of trisomic cells in his tissues, which is typical of mosaic Down syndrome (Thompson & Thompson Genetics in Medicine 8e).
Why each distractor is wrong
Option 2: While meiotic non-disjunction in maternal meiosis II would produce free trisomy 21, not mosaicism. Free trisomy 21 accounts for 95% of Down syndrome cases and has a recurrence risk of 1% plus maternal age; it does not produce the mixed karyotype (46,XY/47,XY,+21) seen in B.
Option 3: Robertsonian translocation (marked C in the diagram) is a structural rearrangement, not the mechanism of B. Translocation carriers have a 10–15% recurrence risk if the mother carries the balanced translocation. The karyotype shown in B is a simple mosaic, not a translocation-based pattern.
Option 4: Trisomy rescue (loss of the extra chromosome in some cells) can occur and is a less common mechanism of mosaicism, but it typically produces a different pattern (e.g., uniparental disomy in some cells). The karyotype in B shows a straightforward mixture of normal and trisomic cells, consistent with mitotic non-disjunction, not rescue. Additionally, uniparental disomy carries different recurrence implications and is marked separately as D.
High-YieldNEET PG
Mosaic Down syndrome (1–2% of all DS cases) arises from post-zygotic mitotic non-disjunction, has milder features and higher IQ than free trisomy 21, and has very low recurrence risk when de novo (population risk + maternal age) — but always check parental karyotypes to exclude germline mosaicism.
Thompson & Thompson Genetics in Medicine 8e
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