Non-invasive prenatal detection of dominant single-gene disorders in fetal structural abnormalities: a clinical...

This study evaluated the accuracy of non-invasive prenatal testing (NIPT-SGDs) for dominant monogenic genetic diseases associated with fetal structural abnormalities and to assess the feasibility of clinical application.

Pregnant women requiring prenatal diagnosis due to fetal structural abnormalities were enrolled. Maternal peripheral blood was analyzed for cell-free DNA (cfDNA) using coordinative allele-aware target enrichment sequencing (COATE-seq). This assessed fetal allele depth distribution, fraction and variation ratio. The variation's origin was then determined to obtain fetal variation information. Finally, NIPT-SGDs results were confirmed via invasive prenatal diagnosis (IPD).

Upon examination of 113 samples using NIPT-SGDs, COATE-seq successfully analyzed 112 for fetal variation, excluding one due to hemolysis. The study detected six positive cases, yielding a 5.36% detection rate. These disorders included tuberous sclerosis complex (TSC1 and TSC2 being its causative genes), Noonan syndrome (PTPN11), polycystic kidney disease (PKD1), and Kabuki syndrome (KMT2D), occurring twice each, except for Noonan and polycystic kidney disease. Two false positives were due to the mother being a genetic mosaicism. Compared to invasive whole-exome sequencing (WES), NIPT-SGDs did not detect nine positive cases of IPD dominant monogenic diseases, accurately identifying 90.18% (101/112) of the actual positive and negative cases.

Our findings demonstrate the clinical utility of NIPT-SGDs using COATE-seq in effectively identifying fetuses with dominant single-gene disorders. Furthermore, this method can be applied to all fetuses.