Is routine karyotyping required in prenatal samples with a molecular or metabolic referral?

Currently, there is no evidence available in the literature indicating that the prevalence of chromosomal abnormalities is higher in pregnancies with a referral for DNA mutation or metabolic testing. Although the European cytogenetic guidelines for prenatal diagnosis [1] indicate that both DNA mutation and metabolic testing do not serve as referral categories for traditional karyotyping (TK), most prenatal centres worldwide routinely offer TK as an additional test. In clinical practice, most couples referred for DNA mutation analysis also opt for TK [2].It can be disputed, however, whether TK is required when there is no a priori increased risk for chromosomal anomalies as compared to the normal population. On the other hand, it has been argued that when a risky invasive prenatal test is performed anyway, it is unethical not to concomitantly exclude the occurrence of putative chromosomal abnormalities [3]. With TK, a wide range of chromosomal abnormalities can be detected, including alterations in copy number (aneuploidy) and structural chromosomal rearrangements such as translocations and inversions, being either balanced or unbalanced. Targeted PCR-based assays such as multiplex ligation-dependent probe amplification (MLPA) or quantitative fluorescent PCR (QF-PCR), are highly suited for rapid aneuploidy detection (RAD) of the chromosomes 21, 18, 13, X and Y [4-12]. Previously, it has been suggested that if the referral reason is an increased risk of Down's syndrome, resulting from a positive screening test result or an advanced maternal age, karyotyping could effectively be replaced by RAD, provided that no structural fetal abnormality has been detected upon ultrasound examination [5,13-17]. The use of RAD as a targeted, standalone test instead of karyotyping when invasive prenatal testing is performed in cases with DNA mutation or metabolic test referrals, has not been studied before. This retrospective study addresses the clinical impact of TK for samples offere