There are nearly 7000 rare diseases that have been reported in the world. Although most of them occur with a frequency of less than one in 2000, in total about 6% of the population suffers from rare diseases. These rare diseases are often caused by changes in genes, which is currently lack of effective treatment. The rapid development of next generation sequencing technology boosts the discovery of new causative gene for these rare diseases, as well as the genetic diagnosis in clinic practice. Carrier screening, prenatal diagnosis and newborn screening are wildly used in the world to prevent and diagnosis of rare diseases. Among them, genetic test for pregnant women is the most powerful and cost-effective tool to identify and prevent rare diseases related birth defect. However, most of the current routine prenatal genetic testing for rare diseases requires of collecting fetal samples through an invasive process, which might lead to maternal anxiety, or even miscarriage. Therefore, developing an effective approach to perform noninvasive prenatal test (NIPT) for rare diseases is the key challenge to prevent birth defect in the future.
The discovery of cell-free fetal DNA, coupling with next generation sequencing, makes NIPT for rare diseases possible. In this study, we applied sequencing-based noninvasive prenatal testing for common aneuoploidy detection, such as trisomy 21, 18, and 13. The new approach using low-coverage whole genome sequencing for maternal plasma DNA could achieve a sensitivity and specificity of over 99%, which can provide accurate and reliable results and thus avoid most of invasive process compared to standard prenatal test. Moreover，we also designed probes for genes related to Monogenetic disorders and conducted target region sequencing for parents, proband, and maternal plasma. In order to obtain accurate result, we combined the haplotype information from the parents with maternal plasma deep sequencing data to recover the fetal genotype.
Our study demonstrated that the sequencing-based new approach could be used to detect rare diseases, including chromosomal diseases and monogenetic diseases in a noninvasively manner. The new approach has great potential to be wildly used in the worldwide with the decreasing in sequencing costs, and therefore play an incredible role to prevent rare diseases.