Masterclass 6 - Algorithms of (Public-funded) Prenatal Screening and Diagnosis in Hospital Authority

The journey of prenatal screening and diagnosis for our pregnant women & their families looks very much like the history of development of the MTR map in Hong Kong.
Milestones:
• 1970s: Amniocentesis & chorionic villus sampling for karyotyping introduced.
• 1980s: Routine ultrasound screening.
• 1990s: First & second trimester combined screening for Down syndrome.
• 2010: Universal Down syndrome screening for all pregnant women irrespective of maternal age.
• 2019: PCR & chromosomal microarrays on top of karyotyping.
• 2019: 2nd tier Non-invasive Prenatal Testing (NIPT) – maternal serum for fetal (placental) DNA.
• 2021: MDT – FMPRG (Fetal Medicine, Pathology, Radiology, Genetics/Genomics) web based platform selecting complex prenatal cases for WES or WGS.
HA's prenatal screening and diagnosis development has balanced cutting-edge technology with ethical governance, ensuring equitable access to our pregnant women. Future trends may focus on personalized genomics and AI-driven risk assessment and counselling.

In recent 5 years, the Hospital Authority prenatal screening and diagnosis programme has been evolving with implementation of modern technologies. The use of second tier non-invasive prenatal testing (NIPT) through sequencing of maternal plasma cell-free DNA with higher sensitivity and specificity compared to conventional Down syndrome screening test can decrease the number invasive diagnostic procedures and their associated miscarriages. The chromosomal microarray analysis (CMA) performed on prenatal samples can expand the scope of prenatal genetic diagnosis from common aneuploidies to microdeletion and microduplication syndromes. Furthermore, the application of whole-exome sequencing (WES) or whole-genome sequencing (WGS) can further reveal the underling monogenetic disorders for unsolved complex fetal cases. In this lecture, we are delighted to share the performance of our recent work with the implementation of the above-mentioned advanced genetic technologies.

To achieve a universal and comprehensive prenatal screening and diagnostic algorithms in Hong Kong, we explored the new territories and highlighted the novel trends in prenatal screening and diagnosis. Coming a long way from the pioneering work of CUHK on non-invasive prenatal testing (NIPT) toward a large-scale genome wide analysis by next generation sequencing. Non-invasive prenatal testing (NIPT) for common trisomies (21, 18, 13) has become a well-established, highly accurate screening tool in Down syndrome and other aneuploidy screening programs worldwide. NIPT by sequencing allows identification of sequence variants, being pathogenic or polymorphic, which in turn allowing for improved non-invasive prenatal screening. In this lecture, we are going to demonstrate value of concurrent SNP typing to improve the further success of NIPT to detect microdeletions and monogenic diseases. Although this represented a substantial advancement, the NIPT approach had important limitations as a screening test. Recognising this limitation, another methodological novelties developed in sequencing technologies, namely Low-pass genome sequencing (LP-GS) is developed at a reduced depth of coverage that supports affordable detection of genome-wide copy number variants (CNVs) and cryptic chromosome structural rearrangements. We validate LP-GS as a clinical diagnostic tool in cytogenetics and demonstrated it has the potential to revolutionize invasive prenatal testing by expanding the scope, accuracy, and affordability of detecting fetal genetic abnormalities beyond traditional methods like karyotyping and chromosomal microarray and even at a lower cost.