The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

Background: Postoperative blood product transfusions in elderly hip fracture patients cause concern for morbidity and mortality. The purpose of this study was to identify predictors and short-term sequelae of postoperative transfusion following geriatric hip fracture surgery. Methods: We queried the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) to identify geriatric (⩾65 years) patients who sustained operative femoral neck, intertrochanteric, and subtrochanteric hip fractures in 2016. Multivariate regression was used to determine risk-adjusted odds ratios (OR) of associated perioperative risk factors and sequelae of postoperative transfusion. Results: In total, 8416 geriatric hip fracture patients were identified of whom 28.3% had documented postoperative transfusion. In multivariate analysis, age (OR 1.03 [1.02–1.04], p < 0.001), preoperative anaemia (OR 4.69 [3.99–5.52], p = 0.001), female sex (OR 1.61 [1.39–1.87], p < 0.001), lower BMI (OR 0.97 [0.96–0.98], p < 0.001), American Society of Anesthesiologists (ASA) classification (OR 1.14 [1.01–1.27], p = 0.031), COPD (OR 1.30 [1.06–1.59], p = 0.011), hypertension (OR 1.17 [1.01–1.35], p = 0.038), increased OR time (OR 1.02 [1.01–1.03], p < 0.001), and intertrochanteric (OR 2.99 [2.57–3.49], p < 0.001) and subtrochanteric femur fractures (OR 5.07 [3.84–6.69], p < 0.001) were independent risk factors for receiving postoperative blood transfusion. Patients with postoperative transfusion had a significantly higher risk-adjusted 30-day mortality (8.4% vs. 6.4%, OR 1.29 [1.02–1.64], p = 0.035), hospital readmission rate (9.4% vs. 7.7%, OR 1.27 [1.04–1.55], p = 0.018), and total hospital LOS (7.3 vs. 6.3 days, p < 0.001). Conclusions: Postoperative transfusion is a common occurrence in geriatric fragility hip fractures with multiple risk factors. Careful preoperative planning and multidisciplinary management efforts are warranted to reduce use of postoperative transfusions.

The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.

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