"Genetic & Congenital Disorders" — Practice

Question 1

Which cardiac lesion is characteristically associated with Down syndrome?

Accepted Answer

B

Question 2

In a pedigree, an affected father has an affected son. Which inheritance pattern is excluded?

Accepted Answer

A

Question 3

A child has neonatal hypotonia and poor feeding, later developing hyperphagia, obesity and hypogonadism. Which region is involved and from which parent?

Accepted Answer

B

Question 4

A cell-free DNA test is positive for trisomy 13. What should be advised?

Accepted Answer

B

Question 5

A term neonate feeds normally for 48 hours then develops vomiting, lethargy and seizures. What class of disorder does this suggest?

Accepted Answer

B

Question 6

A child with Down syndrome has 46 chromosomes on karyotype. What is the implication?

Accepted Answer

A count of 46 rather than 47 establishes that this is not free trisomy 21 from non-disjunction, and the extra chromosome 21 material must therefore be attached to another chromosome. This is a Robertsonian translocation, in which two acrocentric chromosomes fuse at their centromeres.

The implication is entirely about recurrence risk. Free trisomy 21 carries a low recurrence risk related to maternal age, because non-disjunction is a sporadic event. A translocation may have arisen de novo, in which case the risk is similarly low, or it may have been inherited from a phenotypically normal parent who carries the translocation in balanced form.

Both parents must therefore be karyotyped. A balanced carrier parent has a substantially raised risk in every subsequent pregnancy, and in the specific case of a 21;21 translocation carrier the risk approaches certainty. This is precisely why a full karyotype rather than a rapid aneuploidy test is performed in every child with Down syndrome.

Question 7

Why does cell-free DNA screening have a much lower positive predictive value for trisomy 13 than for trisomy 21, despite similar test performance?

Accepted Answer

Because positive predictive value is not a property of the test alone but of the test applied to a population, and it depends heavily on how common the condition is.

Sensitivity and specificity describe the test itself and are broadly similar for the three trisomies. But the number of true positives generated depends on prevalence, whereas the number of false positives depends on the specificity applied to the much larger unaffected population.

Trisomy 21 is the commonest of the three, so screening a population produces a reasonable number of true positives against the background of false ones. Trisomy 13 is far rarer, so the same specificity generates a similar absolute number of false positives while producing far fewer true ones, and the ratio between them shifts sharply.

The consequence is practical rather than academic. A woman told she has a positive result for trisomy 13 has a substantially lower probability of actually carrying an affected fetus than a woman told the same about trisomy 21, and both require diagnostic confirmation before any decision.

Question 8

A pedigree shows a condition transmitted by all affected mothers to all their children, and by no affected father to any child. Severity varies greatly. What explains this?

Accepted Answer

B

Question 9

Why must folic acid supplementation begin before conception rather than at the first antenatal visit?

Accepted Answer

Because the structure it protects has already formed by the time most women present. The neural tube closes by around 28 days after conception, which is roughly six weeks of gestational age counted from the last menstrual period.

At that point many women have only just missed a period, and a substantial proportion of pregnancies are unplanned and unrecognised. A first antenatal visit at eight, ten or twelve weeks therefore occurs weeks after the critical window has closed, and supplementation started then cannot prevent a defect that has already occurred.

This is why public health strategy addresses the problem in two ways that do not depend on a woman knowing she is pregnant: advising periconceptional supplementation to all women who might conceive, and fortifying staple foods at population level.

Higher doses are required for women with a previous affected child, those taking antiepileptic drugs, particularly valproate, and those with diabetes or obesity, and in those groups supplementation should begin well before conception is attempted.

Practice — "Genetic & Congenital Disorders"

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