Portrait of author

Fanwei Zeng:
Clinical application of high-throughput sequencing technology in prenatal screening and diagnosis of birth defects

Date: 30-05-2022    Supervisor: Anders Albrechtsen

Birth defects refer to structural, functional abnormalities that are present from birth, which may lead to early miscarriage, stillbirth, and infant mortality. It indicates that nearly 8 million babies, accounting for 6% of the world's newborns, are born with birth defects. Genetic factors
including chromosomal abnormalities and monogenic disorders and environmental factors such as intrauterine infection are the principal known causes. The thesis is a series of studies aiming to develop and apply high-throughput sequencing technology in the prenatal screening and diagnosis of birth defects. It is composed of three studies, each of them dealing with different aspects of the etiology of birth defects.

In paper I, chromosomal aberrations causing fetal anomalies are prioritized. Although noninvasive prenatal screening (NIPS) contributes to superior performances in detecting chromosomal abnormalities as a representative of genomic technologies, inconsistent results between NIPS and prenatal diagnosis persisted. In this study, NIPS false-negative data and clinical information were obtained from the large-population cohort of 3,320,457 pregnant women screened. It demonstrated that a significant proportion of NIPS false-negative cases  are identifiable by the subsequent ultrasonography and NIPS can be integrated with ultrasound to promote better clinical performance.

In paper II, we concern with monogenic disorders whose first-trimester screening methods are not accessible, despite the relatively high incidence. A unique molecular index-based strategy has been established to detect low-frequency variants in 29 pathogenic genes associated with 36 monogenic disorders. Clinical validation was demonstrated the method was performed with 100% sensitivity and 100% specificity and is especially applicable to the pregnancies with ultrasound anomalies of craniocerebral, cardiac abnormalities, and skeletal dysplasia.

In paper III, chromosomal abnormalities and intrauterine infection were expected to be identified by a low-depth whole-genome sequencing technology simultaneously. Diagnostic yields of the detection were evaluated by a multicenter cohort of clinical samples from the group
with miscarriages/stillbirth and the group with a prenatal diagnosis with nine indications. It illustrated that the methods can be utilized to detect fetal chromosomal aneuploidy, copy number variants >100kb, and intrauterine infection represented by cytomegalovirus.

Collectively, this work provides a genomics solution by sequencing technologies to complement the current routine prenatal screening and diagnosis, contributing reference to the etiology, detection, and prevention of fetal abnormalities.