Authors (including presenting author) :
So PL, Leung WC, Kan Anita, Choy Richard
Affiliation :
Fetal Medicine, Pathology, Radiology and Genetics (FMPRG) Multidisciplinary Team
Introduction :
Approximately 3% of pregnancies are complicated by fetal structural malformations which are detectable by prenatal ultrasonography. The identification of underlying genetic causes can improve the pregnancy management and facilitate parents to make informed reproductive decisions. In April 2021, whole exome sequencing (WES) and whole genome sequencing (WGS) for special cases were integrated into Hospital Authority (HA) prenatal diagnosis clinical service.
Objectives :
To evaluate the additional diagnostic yield of next generation sequencing (WES or WGS) for single gene disorders following negative results of standard investigations with polymerase chain reaction for common aneuploidies and chromosomal microarray for microdeletions/microduplications in a selected cohort of pregnancies with fetal structural anomalies on ultrasound using a multidisciplinary team-based approach.
Methodology :
Two prenatal diagnostic laboratories (The University of Hong Kong /Tsan Yuk Hospital & The Chinese University of Hong Kong /Prince of Wales Hospital) provided trios WES or WGS for special prenatal cases (after exclusion of aneuploidy and copy number variations) detected in all eight HA prenatal diagnostic clinics and agreed by voting from a multidisciplinary clinical review panel (clinical scientists, clinical geneticists, fetal medicine specialists, pathologists and radiologists). We retrospectively reviewed the clinical performance and usefulness of this new service over one year.
Result & Outcome :
After multidisciplinary assessment and voting, 29 out of 39 cases were selected, including 15 WES and 14 WGS. Overall, the molecular diagnostic rate was 37.9% (11/29). De novo autosomal dominant disorders accounted for 72.7% (8/11), inherited autosomal recessive disorders for 18.2% (2/11), and inherited X-linked disorders for 9.1% (1/11). The median turnaround time for ongoing pregnancy was 19.5 days (range, 13–31 days). Our study showed an overall clinical impact of 55.2% (16/29), which influenced reproductive decision-making in four cases, guided perinatal management in two cases and helped future family planning in ten cases. Two novel genetic variations predicted as pathogenic in NEB and KMT2D were discovered. Our findings suggest that using a multidisciplinary approach to case selection, WES and WGS can enhance the prenatal genetic diagnosis in fetuses with structural abnormalities in a population setting which can help the family reproductive planning.
