Medicus April 2016

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CHALLENGES WITH EXPANDED SCREENING IN NON-INVASIVE PRENATAL TESTING (NIPT) Sarah Long

the future where screening for even less well defined copy number variants may be offered. Women offered more extensive prenatal microarray test, without additional risk to the pregnancy, accepted it as ‘an offer too good to pass up’.¹⁵ However, the diagnosis of a condition, even a relatively well known one such as a 22q11 deletion, was found to complicate decision making in pregnancy due to the variable phenotype.¹⁵ Detection rate and positive predictive value The positive predictive value of NIPT will be low for rare disorders.⁶ Whether detection of these rare disorders in pregnancy is seen as beneficial by the patients, in light of the potential for increased anxiety and complex counselling issues, is unknown. The detection rate for microdeletion/duplication disorders using NIPT has not been studied in a large population. However, an estimated rate of detection for the five syndromes listed in Table 1 is around 70 per cent¹⁶, meaning 30 per cent of affected pregnancies will not be detected. This is comparable to second trimester maternal serum screening for trisomy 21, and less than the 81 per cent detection rate of trisomy 21 for first trimester combined screening.¹⁷ Another aspect to consider is how parents understand these figures. Evidence from first trimester screening (FTS) indicates that parents who received a low risk result and then had a child with Trisomy 21, saw the FTS as a definitive test rather than a level of risk.¹⁸ Observations from counselling such couples suggest that a diagnosis of Trisomy 21 at birth was a shock as they thought the test had been done in pregnancy. It does not seem unreasonable to propose that screening for microdeletions might also result in false reassurance, and complicate the diagnostic journey after the birth of an affected child. Conclusion As Aubrey Milunsky so eloquently phrased in the recent ISPD debate, “ Women who choose NIPT, especially for microdeletion/microduplication detection, should be well informed about the accuracy, reliability, false positive and false negative rates, and the limited ability to predict future intellectual development .”¹² Whether providers feel confident they can achieve this in the time available; feel ready to explore the complexity and potential outcomes of the test and whether couples want this information, are all questions to be answered before ‘ticking the box’. ■ References available on request.

have this deletion until their child’s diagnosis. Therefore NIPT, which uses the maternal genome for comparison, has the potential to give information about the mother as well as the fetus. In the absence of ultrasound findings, a high risk NIPT result will require parents to make management decisions without the benefit of further information. Most genetic test results do not exist in a vacuum but are, rather, ‘puzzle pieces’, including family history (absent in the case of de novo conditions) and phenotype. Without seeing the affected individual and being able to do a physical exam, or using indirect methods such as ultrasound, predicting the prognosis is difficult. Interestingly, penetrance does seem to be higher in de novo microdeletions/duplication, which means that when counselling about NIPT results the question of the need for parental testing may be raised.¹³ Parental testing (usually using methods such as FISH for the specific chromosomal disorder found in the fetus) will result in an increase in wait time for the parents, resulting in a later gestational age if the parents decide to end the pregnancy. Where the phenotype is relatively consistent, i.e. Prader- Willi and Angelman syndrome, adequate pre-test counselling about these rare conditions is still required. The question should be – can providers adequately counsel about the clinical picture, prognosis and management options of these rare disorders? These conditions are rare, incurable and affected individuals can survive into adulthood. The options available are to either continue or end an affected pregnancy. Experience with prenatal microarray detection of microdeletions and microduplications There are several issues common to both NIPT and Microarray technologies. Microarray is a technique designed to find missing or duplicated sections of chromosomes (copy number variants or CNVs). Prenatal microarray (targeted) that detects microdeletions and microduplications has been found to contribute significant knowledge in 6 per cent of cases where standard karyotype was normal and there were structural anomalies on ultrasound.¹⁴ In this study, 88.2 per cent of CNVs were found to be benign. When women were selected on maternal age alone (no ultrasound anomaly), the detection rate for clinically significant microarray results was lowered to 1.7 per cent.¹⁴ Despite the relatively limited panel currently being offered by NIPT providers, it is not unreasonable to look towards

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