A 45-Chromosome Mother and a Family Asking About Recurrence
Mrs K., 41, from Nashik, has just delivered a boy with hypotonia, a single palmar crease and a flat nasal bridge. The infant's blood karyotype, scored on 30 metaphases, reads 46,XY,der(14;21)(q10;q10),+21: he carries two free copies of chromosome 21, one normal 14 and one translocation chromosome. Both parents were karyotyped. The mother's report reads 45,XX,der(14;21)(q10;q10) and she is clinically normal; the father is 46,XY. Their 7-year-old daughter was karyotyped at another laboratory and the report says only '46,XX, normal'. A relative who works in a nursing home has told the family that Down syndrome 'does not run in families' and that the risk for the next pregnancy is simply the age-related risk, about 1 in 85 for a woman of 41. The mother asks three things: why she has only 45 chromosomes, what the real risk is, and whether her daughter can be reassured.
1. Explain why Mrs K. is phenotypically normal with only 45 chromosomes, and calculate a realistic recurrence risk to replace the 1 in 85 she was quoted.
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Why 45 chromosomes can be harmless
Chromosomes 14 and 21 are acrocentric. The breaks in this family lie in the q10 region next to the centromere, so the two long arms fuse into one metacentric-looking chromosome, der(14;21). The two short arms are lost, but their only significant content is the rRNA gene clusters, and hundreds of functional copies remain on the other acrocentrics (13, 15, 21, 22). No unique coding sequence is lost, so the carrier is balanced: the same genetic content as a normal person, packed into 45 chromosomes instead of 46.
Why the risk is not the age-related figure
At meiosis the three structures (normal 14, der(14;21), normal 21) form a trivalent and segregate in several ways. Possible gametes are:
- normal 14 + normal 21 → normal child
- der(14;21) alone → balanced carrier, like the mother
- der(14;21) + normal 21 → two copies of 21q → Down syndrome
- 14 alone, 21 alone, or der(14;21) + normal 14 → monosomy or trisomy 14/21, almost always lethal before term
So only three outcomes survive to birth, but the observed proportion is not a simple 1 in 3, because unbalanced conceptions are often lost. Empirically, a female carrier has roughly a 10–15% risk of an affected liveborn; a male carrier roughly 1–2%. The quoted 1 in 85 is about 1.2%, so her true risk is around ten times higher. She should be counselled with the carrier figure and offered prenatal diagnosis in every pregnancy.
2. The daughter's report says only '46,XX, normal'. Can she be reassured that she is not a carrier? What must be verified before the family is told anything?
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A chromosome count alone cannot answer the question; the specific chromosomes 14 and 21 must have been examined.
Reasoning through the possibilities
- If the daughter inherited the mother's normal 14 and normal 21, her karyotype is 46,XX with two normal 14s and two normal 21s. She is not a carrier and her risk is the population risk.
- A clinically normal carrier of this translocation must have 45 chromosomes: der(14;21) plus one normal 14 plus one normal 21.
- A person with 46 chromosomes who carried der(14;21) plus a normal 21 would have two copies of 21q and would be affected, not a healthy 7-year-old.
So, in principle, a genuinely normal 46,XX girl with two normal 14s and two normal 21s is not a carrier, and the family can be reassured. But the report as quoted does not state this. The laboratory should be asked for the full karyotype description (or the metaphase images), and if the record is ambiguous, a repeat karyotype or FISH with a chromosome 21 painting probe should be done. Each child of a carrier mother has a 50% chance of inheriting the translocation chromosome, so the distinction matters for the daughter's own future pregnancies. Reassurance should be given only after the report is confirmed, and the daughter should be told to disclose her mother's carrier status if she ever seeks genetic counselling.
3. In the next pregnancy the couple ask whether a maternal blood test (cell-free fetal DNA / NIPT) can replace an invasive test. Advise them.
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What NIPT can and cannot answer
NIPT sequences cell-free DNA, mostly of placental origin, in maternal plasma and estimates whether there is excess chromosome 21 material. For ordinary trisomy 21 it is a very good screening test, and it can also flag translocation-type trisomy 21. However:
- It is a screening test, not a diagnosis; it returns a probability and has false positives and false negatives.
- It detects dosage imbalance only. A fetus that has inherited the der(14;21) in the balanced state has normal dosage and would be reported as normal, yet that child is a carrier who will face the same reproductive decisions later.
- In this family the question is twofold: is the fetus trisomic, and is the fetus a balanced carrier? NIPT answers the first imperfectly and the second not at all.
Recommendation
Because the mother is a known carrier, the appropriate test is a diagnostic one: chorionic villus sampling at about 11–13 weeks, or amniocentesis at about 15–18 weeks, with full karyotyping (FISH for 13, 18, 21 and the der(14;21) can give a rapid interim answer). NIPT may be done first if the couple wish, but a negative NIPT must not be used to cancel the invasive test. Procedure-related miscarriage risk should be quoted honestly, and the couple should see a genetic counsellor before deciding.