Because of improvements in the safety of invasive procedures and advances in technology, the most recent systematic reviews demonstrated pregnancy loss rates for CVS and amniocentesis to be less than 1.0% [2, 12]. Naturally, parents-to-be are anxious to have results as early as possible. Cell-free DNA screening takes the advantage of being able to be performed as early as 10 weeks, without the need of an invasive procedure. Noninvasive prenatal screening test has sensitivities and specificities approaching 99%. While NIPT detects aneuploidies with a high degree of certainty, it is, so far, less reliable in detecting microdeletions and duplications in fetal genomes smaller than 5 Mb [13, 14]. Recently, large number of validation studies reporting the PPV of NIPT for the detection of CNVs have been published. Gou et al. demonstrated that the PPV of recurrent CNVs seemed to be higher than that of rare chromosomal deletions/duplications [15]. Furthermore, a recent study by Rafalko et al. reported higher PPV for complex CNVs (93.9%) compared to isolated CNVs (61.0%) [16].
A concern is that as higher proportions of the genome are analyzed, false positive and false negative results are expected to increase, which would result in an increase in unnecessary invasive procedures [17]. NIPT is still a screening test. During pre-test counseling, women should be informed about the accuracy, reliability, false positive, and false negative rates. According to current NIPT guidelines, ACMG strongly recommends all positive NIPT findings to be confirm by invasive prenatal diagnostic testing [17]. In addition, diagnostic follow up testing with CMA should be offered when NIPT identifies a CNV [17].
Partial trisomy of the distal 15q is a rare chromosomal disorder. In general, the duplication of 15q has been characterized by prenatal and postnatal overgrowth, craniosynostosis, distinct facial features, and intellectual disability, likely reflecting triplosensitivity for one or more of the several genes that are found within this region [18,19,20]. The breakpoints and extent of the duplicated segment are variable among patients. The clinical outcome and severity of physical findings varies from case to case, depending on the length and the genes involved in the duplicated region of the chromosome [19, 21]. Specifically, duplication of type 1 insulin-like growth factor 1 receptor (IGF1R) (OMIM 147,370) gene located at 15q26.3 is thought to lead to overgrowth, whereas haploinsufficiency of IGF1R can cause growth restriction [19,20,21,22]. The majority of cases reported have resulted from de novo unbalanced translocations, and the second chromosome involved in the translocation has varied. Although many large duplications can be appreciated by routine karyotyping, detection of this duplication generally requires analysis by fluorescence in situ hybridization and chromosomal microarray. Abnormalities involving sub-telomeric regions can be difficult to visualize well using conventional cytogenetics methods (G-banding analysis).
Previous study has detected the deletion of 5 Mb in fetal chromosome 15q11.2q13.1 and was further confirmed by CNV and karyotype analysis [14]. Our study reports a duplication of about 10 Mb in size detected using NIPT. A finding of duplication of a 10.34 Mb fragment located on 15q26.1q26.3 by NIPT was confirmed using various genetic modalities. The existence of duplication of material from chromosome 15 was established and further delineated by microarray, followed by the karyotype analysis and FISH. Detection of microdeletions or duplications can be very difficult using G-banding karyotyping analysis from amniotic fluid. Therefore, to pinpoint the exact location of the duplicated fragment and to visualize the whole chromosomal complement, subtelomeric probes for the distal portion of chromosomes 15q and 18q were used. The final karyotype from amniotic fluid was reported as 46,XX,der(18)t(15;18)(q26.1;q23)dn.
Without molecular cytogenetic testing modalities, a dup(15)(q26.1q26.3) would have been suggested, but a derivative chromosome 18 would not have been detected. CNV analyses provide information whether copy number gains and losses are present but not whether they have been translocated from their normal position(s) in the genome. Thus, confirmation of suspected chromosome abnormalities by FISH and chromosome analysis may be necessary to determine the nature of an abnormality.
The pregnancy reported in this paper ended in an elective interruption of pregnancy. Since unbalanced translocations can result from either de novo event or the malsegregation of a balanced parental translocation, parental chromosomal studies were completed to see if either of them is a balanced carrier of a translocation involving chromosome 15 and 18. Due to lack of precise and targeted genomic testing done in Bosnia and Herzegovina, diagnostic follow up testing was done in collaboration with laboratories in Greece and Germany. Parental karyotype and FISH analysis were normal with no genetic aberrations. The couple has another healthy child with unknown karyotype. The de novo origin of the 15q duplication is consistent with the fact that there is no prior history of spontaneous abortions and no family history of chromosomal anomalies or genetic disorders. Moreover, it is important to note that negative results in both parents cannot exclude the possibility of parental gonadal mosaicism, thus leading to minor recurrence risk in subsequent pregnancies.
