Trio exome sequencing is highly relevant in prenatal diagnostics.

Gabriel H¹, Korinth D¹, Ritthaler M¹, Schulte B¹, Battke F², Kaisenberg C³, Wüstemann M⁴, Schulze B⁵, Friedrich-Freksa A⁶, Pfeiffer L⁷, Entezami M⁸, Schröer A⁸, Bürger J⁹, Schwaibold EMC¹⁰, Lebek H¹¹, Biskup S^{1 2}

Objective: About 3% of newborns show malformations, with about 20% of the affected having genetic causes. Clarification of genetic diseases in postnatal diagnostics was significantly improved with high-throughput sequencing, in particular through whole exome sequencing covering all protein-coding regions. Here, we aim to extend the use of this technology to prenatal diagnostics.

Method: Between 07/2018 and 10/2020, 500 pregnancies with fetal ultrasound abnormalities were analyzed after genetic counseling as part of prenatal diagnostics using WES of the fetus and parents.

Results: Molecular genetic findings could explain ultrasound abnormalities in 38% of affected fetuses. In 47% of these, disease-causing de novo variants were found. Pathogenic variants in genes with autosomal recessive or X-linked inheritance were detected in more than one-third (70/189 = 37%). The latter are associated with increased probability of recurrence, making their detection important for further pregnancies. Average time from sample receipt to report was 12 days in the recent cases.

Conclusion: Trio exome sequencing is a useful addition to prenatal diagnostics due to its high diagnostic yield and short processing time (comparable to chromosome analysis). It covers a wide spectrum of genetic changes. Comprehensive interdisciplinary counseling before and after diagnostics is indispensable.