EP18.27: Whole genome sequencing, potential for a primary diagnostic test in the management of prenatally detected congenital malformations

Investigation of the diagnostic yield of whole genome sequencing (WGS) in prenatally detected congenital malformations. Prospective study where 85 pregnancies with fetuses having different congenital malformations, negative for trisomies and causative copy number variants (CNVs), were further analysed with fetal- parental trio WGS analysis. The phenotypes of the cases were divided into six different groups: multisystem (n = 19), central nervous system (CNS) (n = 21), skeletal (n = 12), thorax (n = 16), abdominal (n = 11) and other isolated anomalies (n = 6). A molecular diagnosis was achieved in 23/85 (27%) of cases. Causative variants were identified in 21 different genes: FGFR3 (n = 2), L1CAM (n = 2), ACTA1 (n = 1), CDH2 (n = 1), CHD7 (n = 1), COL1A1 (n = 1), COL1A2 (n = 1), DHCR7 (n = 1), EYA1 (n = 1), FBXO11 (n = 1), FRAS1 (n = 1), NIPBL (n = 1), OFD1 (n = 1), PDHA1 (n = 1), POMGNT1 (n = 1), PTPN11 (n = 1), RIT1 (n = 1), SMARCC1 (n = 1), SMC3 (n = 1), SOX9 (n = 1) and STAG2 (n = 1). The diagnostic yield of the six different phenotypic groups were: multisystem 8/19 (42%), CNS 8/21 (38%), skeletal 4/12 (33%), thorax 2/16 (13%), abdominal 1/11 (9%) and other isolated anomalies 0/6 (0%). A molecular diagnosis was found overall in 27% of cases with prenatally detected congenital malformations where chromosome aberrations already had been excluded. As these are a well-known cause of fetal anomalies, future studies using WGS as a primary diagnostic test including assessment of chromosome aberrations will likely provide a genetic explanation to the etiology in over 50% of cases. An underlying genetic cause to the detected fetal malformation may provide the parents with an explanation, more accurate counselling on the recurrence risk and options in future pregnancies. Turnaround time and costs will need to decrease before WGS can be implemented as a primary diagnostic test in the management of pregnancies with congenital malformations.