Whole exome sequencing (WES) has become part of the postnatal diagnostic work-up of both pediatric and adult patients with a range of disorders. In the last years, WES is slowly being implemented in the prenatal setting as well, although some hurdles remain, such as quantity and quality of input material, minimizing turn-around times, and ensuring consistent interpretation and reporting of variants. We present the results of 1 year of prenatal WES in a single genetic center. Twenty-eight fetus-parent trios were analyzed, of which seven (25%) showed a pathogenic or likely pathogenic variant that explained the fetal phenotype. Autosomal recessive (4), de novo (2) and dominantly inherited (1) mutations were detected. Prenatal rapid WES allows for a timely decision-making in the current pregnancy, adequate counseling with the possibility of preimplantation or prenatal genetic testing in future pregnancies and screening of the extended family. With a diagnostic yield in selected cases of 25% and a turn-around time under 4 weeks, rapid WES shows promise for becoming part of pregnancy care in fetuses with ultrasound anomalies in whom chromosomal microarray did not uncover the cause.

In this study, we employed a multifaceted approach combining short-read whole genome sequencing (WGS) analyzed using Delly, cytogenomics using Bionano technology, and Sanger sequencing to identify the breakpoints of a balanced de novo paracentric inversion on chromosome 11, spanning approximately 64 Mb (inv11q13.3; q25). This inversion was discovered in a girl who presented with mild intellectual disability (ID), speech and language delays, a delay in motor development and attention deficit hyperactivity disorder (ADHD). Detailed analysis of the breakpoints revealed the disruption of two genes; SHANK2, which is critical for encoding a postsynaptic scaffolding protein at glutamatergic synapses in the brain, and LINC02714, a long non-coding RNA (lncRNA). Although SHANK2 is not listed in the OMIM database as a causative gene to this date, literature reports at least 21 cases where (likely) pathogenic variants in SHANK2 have been identified in patients with neurodevelopmental disorders (NDDs). A loss of function variant of the SHANK2 gene is in line with the clinical presentation of this patient. No additional genetic variants that could explain her phenotype were identified. In conclusion, by combining WGS, cytogenomics and Sanger sequencing techniques, we identified the exact breakpoints of a large inversion providing a likely molecular diagnosis for our patient.

Objectives: This study evaluates the diagnostic yield of prenatal whole exome sequencing (WES) and its impact on outcome, such as termination of pregnancy (TOP) or neonatal management. Methods: A retrospective analysis of more than 4 years of prenatal WES at a single genetic center was performed. Inclusion criteria included normal genome-wide deletion/duplication analysis and ≥1 ultrasound anomaly. Trio analysis was performed, filtering for de novo , compound heterozygous, homozygous, and hemizygous variants, complemented by a genome-wide phenotype-driven analysis. Results: (Likely) pathogenic variants fitting the phenotype were identified in 36 of 171 cases (21.1 %), of which 19 were de novo , 14 autosomal recessive, one autosomal dominant, and 2 X-linked dominant. Median turnaround time was 16 days. Parents opted for TOP in 21 cases, three resulted in intrauterine death, 11 were carried to term and one was lost to follow-up. Among the neonates, the diagnosis led to optimized postnatal management in 8/11 (72.7 %), abstinence of care in two (18.2 %) and exclusion of syndromic disorders in one (9.1 %). Conclusions: Our findings indicate that in 1/5 pregnancies with ultrasound anomalies and normal deletion/duplication analysis, a (likely) pathogenic variant explaining the phenotype can be identified. The high proportion (17/36 or 47.2 %) of inherited variants highlights the importance of WES for recurrence risk assessment.