Summary Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein ( SRCAP ) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo ) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as “non-FLHS SRCAP -related NDD.” All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP , there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10–20) vs. 59 days (95% CI 23–98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate).Conclusion: Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin. What is Known:• Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used.• Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing. What is New:• This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests.• Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.

We demonstrate that MAS for diaphragmatic hernia appears to be safe in terms of complications and mortality. Besides, it is associated with faster postoperative recovery. Growing experience with this technique is expected to lower the recurrence risk and to shorten the operative time. These findings should be interpreted cautiously because of methodological limitations of the studies included. Selection criteria used in various studies are associated with an important risk of selection bias. Nonetheless, these criteria can be used to identify patients who will benefit most from MAS.

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Objective: The objective of this study is to provide an overview of average healthcare costs for patients admitted to the Neonatal Intensive Care Unit (NICU) and to assess possible impact of implementing Whole Exome Sequencing (WES) on these total healthcare costs.Methods: We retrospectively collected postnatal healthcare data of all patients admitted to the level IV NICU at the Radboudumc (October 2013-October 2015) and linked unit costs to these healthcare consumptions. Average healthcare costs were calculated and a distinction between patients was made based on performance of genetic tests and the presence of congenital anomalies (CAs).Results: Overall, €26,627 was spend per patient. Genetic costs accounted for 2.3% of all costs. Healthcare costs were higher for patients with CAs compared to patients without CAs. Patients with genetic diagnostics were also more expensive then patients without genetic diagnostics. When performing trio-WES for all patients instead of current diagnostics, overall healthcare costs will increase with 22.2%. In case only patients with CAs receive trio-WES, average per patient healthcare costs will increase with 5.3%. Performing trio-WES only for patients with multiple CAs did not result in any cost changes.Conclusions: Genetic diagnostic testing accounted for a small fraction of total costs. By implementing trio-WES as genetic diagnostic test for all patients with CAs there is a limited increase in overall healthcare budget. Not only the diagnostic yield of this cohort will increase, but implementing trio-WES for all patients with CAs may also allow for improved personalized treatments options guided by the diagnoses made.