Testing and screening for chromosome abnormalities

The 1959 report by Lejeune that Down's syndrome is caused by an extra 21st chromosome elicited great surprise as it was widely believed that such a gross addition of DNA could not be compatible with viability. Down syndrome was then, as now, one of the most common known causes of severe handicap, and the ability to observe the extra chromosome by ordinary microscopy was responsible for the rapid emergence of clinical cytogenetics. The sex chromosome abnormalities and other less common trisomies soon followed the discovery of trisomy 21, and, later, other abnormalities, due to loss or gain of parts of chromosomes, were recognised. Over the years, new techniques have been developed to identify progressively smaller chromosome defects, each characterised by specific and non-specific malformations. The most modern techniques do not require microscopy as they exploit the DNA sequence of the human genome, using molecular methods easily capable of a resolution of several thousand DNA base pairs. The difficulty nowadays is to distinguish individual DNA variation of no clinical significance from changes which lead to severe pathology. The distinction usually requires the testing of the patient's parents.

Up to 1975, the usual indication for prenatal diagnosis of Down's syndrome was a maternal age of 35 years or over. It is still not known why increased maternal age raises the risk, but only 30% of Down's syndrome births are in this category and the majority of Down's syndrome pregnancies remained undetected. The introduction in 1975 of screening maternal blood for analytes altered in Down's syndrome stems from an observation that levels of maternal serum alphafetoprotein (AFP) were significantly lower in affected pregnancies. Other biochemical analytes in maternal blood with much higher predictive values for Down's syndrome have since been found. Current screening protocols are now able to predict the syndrome in 90% of pregnancies, irrespective of maternal age, for a false positive rate of 2%. There is now no place for recommending amniocentesis in mothers over 35 years, as this leads to an unacceptable low detection rate and miscarriage in an estimated 1% of women tested.

One of the most promising protocols for Down's syndrome screening uses an ultrasound scan for nuchal translucency plus biochemical markers in the first trimester. Patients with a very low risk (75%) do not require further tests, while the remaining 25% undergo further biochemical screening at 16 weeks. Amniocentesis is required in only 2% of pregnancies, compared with the 30% where advanced maternal age alone is used as the indication. Thus screening leads to a welcome reduction in procedure-related miscarriage.

In a number of centres prenatal fetal chromosome analysis is being replaced by a molecular method (QF-PCR) that provides a diagnosis within 48 hours and is much less expensive. The disadvantage of QF-PCR is that while it can be used effectively for the autosomal trisomies and Turner syndrome, it is not designed to exclude the relatively small number of unbalanced structural chromosome abnormalities that can only be identified by fetal karyotype analysis. There is currently much controversy among health providers about whether the benefits of recognising all such chromosomal syndromes justify the substantial costs involved in karyotype analysis when the screening programme is specifically designed to detect Down's syndrome.

Knowledge that fetal cells are present in the mother's blood in very small numbers throughout pregnancy has prompted efforts over the past 20 years to exploit these cells for non-invasive prenatal diagnosis. Success has been achieved in only a few cases of Down's syndrome, as fetal cells have proved difficult to isolate. Hopes of achieving a practical method for fetal diagnosis using this strategy have largely been abandoned. Interest has turned instead to exploiting fetal DNA in the maternal plasma; this is derived from the breakdown of placental cells. Using molecular methods, DNA sequences from the Y chromosome can be recognised reliably in 100% of pregnancies from six-weeks gestation in women carrying a male fetus; the absence of Y DNA indicates a female fetus. Genes transmitted to the fetus from the father can also be identified, and this has practical use in the diagnosis of genetic diseases such as Huntington's disease. The most widely used indication, however, is the diagnosis of a Rhesus positive fetus in a Rhesus negative mother at risk for haemolytic disease of the newborn. The diagnosis of chromosome abnormalities from fetal DNA has recently been accomplished and should soon be available.

• © 2009 Royal College of Physicians