Clinical application value of targeted amplicon sequencing technology in fetuses with uniparental disomy-related imprinting disorders: a multicenter study
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Background To explore the application value of targeted amplicon sequencing (TA-seq) technology based on multiplex PCR and high-throughput sequencing in prenatal detection of uniparental disomy (UPD)-related imprinting disorders (ImpDis). Methods This retrospective study included 370 samples suspected of UPD from 42 hospitals across China. Of these, 294 samples were successfully tested by TA-seq and methylation multiplex ligation-dependent probe amplification (MS-MLPA), with MS-MLPA serving as the gold standard. Results TA-seq identified 36 positives and 258 negatives, of which 30 positives and 255 negatives were consistent with the findings from MS-MLPA. The sensitivity, specificity, positive predictive value, and negative predictive value of TA-seq were 90.9% (30/33), 97.7% (255/261), 83.3% (30/36), and 98.8% (255/258), respectively. The concordance between the two methods was 96.9% (285/294). Additionally, we observed potential false positives in UPD-related ImpDis testing indications. For instance, the '≥ 5 Mb ROH detected by SNP-array on chromosomes 6, 7, 11, 14, 15, or 20' group exhibited a positive rate of 11.0% (14/127), while the 'familial or de novo balanced Robertsonian translocation or isochromosome involving chromosome 14 or 15 based on CVS or amniocentesis' group and the 'de novo sSMC with no apparent euchromatic material in the fetus' group both demonstrated positive rates of 0% (0/23 and 0/6, respectively). Conclusions TA-seq proves to be a valuable method for prenatal screening of UPD-related ImpDis, significantly reducing false positives and thus easing the economic burden and anxiety for expectant parents. Its straightforward operation, adaptability, and reliability make it promising for future clinical use.
