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Purpose: Integrating genomic data into the electronic health record (EHR) is key for optimally delivering genomic medicine., Methods: The PennChart Genomics Initiative (PGI) at the University of Pennsylvania is a multidisciplinary collaborative that has successfully linked orders and results from genetic testing laboratories with discrete genetic data in the EHR. We quantified the use of the genomic data within the EHR, performed a time study with genetic counselors, and conducted key informant interviews with PGI members to evaluate the effect of the PGI's efforts on genetics care delivery., Results: The PGI has interfaced with 4 genetic testing laboratories, resulting in the creation of 420 unique computerized genetic testing orders that have been used 4073 times to date. In a time study of 96 genetic testing activities, EHR use was associated with significant reductions in time spent ordering (2 vs 8 minutes, P < .001) and managing (1 vs 5 minutes, P < .001) genetic results compared with the use of online laboratory-specific portals. In key informant interviews, multidisciplinary collaboration and institutional buy-in were identified as key ingredients for the PGI's success., Conclusion: The PGI's efforts to integrate genomic medicine into the EHR have substantially streamlined the delivery of genomic medicine., Competing Interests: Conflict of Interest K.S.L.-M. has an immediate family member who is employed by GlaxoSmithKline. All other authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

The autonomic nervous system derives from the neural crest (NC) and supplies motor innervation to the smooth muscle of visceral organs, including the lower urinary tract (LUT). During fetal development, sacral NC cells colonize the urogenital sinus to form pelvic ganglia (PG) flanking the bladder neck. The coordinated activity of PG neurons is required for normal urination; however, little is known about the development of PG neuronal diversity. To discover candidate genes involved in PG neurogenesis, the transcriptome profiling of sacral NC and developing PG was performed, and we identified the enrichment of the type 3 serotonin receptor (5-HT3, encoded by Htr3a and Htr3b ). We determined that Htr3a is one of the first serotonin receptor genes that is up-regulated in sacral NC progenitors and is maintained in differentiating PG neurons. In vitro cultures showed that the disruption of 5-HT3 signaling alters the differentiation outcomes of sacral NC cells, while the stimulation of 5-HT3 in explanted fetal pelvic ganglia severely diminished neurite arbor outgrowth. Overall, this study provides a valuable resource for the analysis of signaling pathways in PG development, identifies 5-HT3 as a novel regulator of NC lineage diversification and neuronal maturation in the peripheral nervous system, and indicates that the perturbation of 5-HT3 signaling in gestation has the potential to alter bladder function later in life.

Atherosclerotic cardiovascular disease (ASCVD) events are the most common cause of death in the United States and for most individuals who experience these events, may be predicted by risk identification tools. ASCVD risk calculators enable a clinician-patient discussion and the presence of risk-enhancing factors may further inform decision-making with respect to preventive pharmacotherapy, especially statin prescription. In cases where the decision of whether to treat with medicine is unclear, coronary artery calcium scoring by computed tomography offers enhanced risk stratification and may allow both clinicians and patients to feel more at ease with the decision to withhold statin therapy. Despite this thoughtful approach, individual risk may still be underestimated. We present a case of a woman whose family history suggested increased short- and long-term ASCVD risk due to intracranial atherosclerosis, but whose tests suggested a more equivocal indication for treatment. Neither she nor her clinician appreciated the presence of significant enough risk to persevere through minor statin side effects for primary prevention, but she was lucky to have survived without appreciable harm from an acute cerebrovascular event and is now able to pursue an appropriate secondary preventive strategy. We discuss how exceptional characteristics may mislead clinicians, including misperception about lower risk due to gender, East Asian predisposition to intracranial more than coronary atherosclerosis, high levels of high density lipoprotein cholesterol (HDL-C), and CACS = 0., (Copyright © 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

We report the case of a 12-year-old girl diagnosed with Nicolaides-Baraitser syndrome with novel ocular features. Diagnosis was based on clinical features, including developmental delay, sparse hair, and craniofacial features along with de novo mutation in SMARCA2. Eye findings included bilateral glaucoma, cataracts, and degenerative vitreoretinopathy. Given the absence of an associated recognizable disorder and the low prevalence of these ocular findings in the general population, we suggest that these ocular features may not be chance association., (Copyright © 2019 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Xia-Gibbs syndrome (XGS) is a recently described neurodevelopmental disorder due to heterozygous loss-of-function AHDC1 mutations. XGS is characterized by global developmental delay, intellectual disability, hypotonia, and sleep abnormalities. Here we report the clinical phenotype of five of six individuals with XGS identified prospectively at the Children's Hospital of Philadelphia, a tertiary children's hospital in the USA. Although all five patients demonstrated common clinical features characterized by developmental delay and characteristic facial features, each of our patients showed unique clinical manifestations. Patient one had craniosynostosis; patient two had sensorineural hearing loss and bicuspid aortic valve; patient three had cutis aplasia; patient four had soft, loose skin; and patient five had a lipoma. Differential diagnoses considered for each patient were quite broad, and included craniosynostosis syndromes, connective tissue disorders, and mitochondrial disorders. Exome sequencing identified a heterozygous, de novo AHDC1 loss-of-function mutation in four of five patients; the remaining patient has a 357kb interstitial deletion of 1p36.11p35.3 including AHDC1. Although it remains unknown whether these unique clinical manifestations are rare symptoms of XGS, our findings indicate that the diagnosis of XGS should be considered even in individuals with additional non-neurological symptoms, as the clinical spectrum of XGS may involve such non-neurological manifestations. Adding to the growing literature on XGS, continued cohort studies are warranted in order to both characterize the clinical spectrum of XGS as well as determine standard of care for patients with this diagnosis., (© 2018 Wiley Periodicals, Inc.)

Ehlers-Danlos syndromes (EDSs) are a group of inherited connective tissue disorders, and among them, classical EDS (cEDS) and hypermobile EDS (hEDS) are the most common. Mitral valve prolapse (MVP) and aortic root dilation (ARD) have previously been reported to occur at an increased frequency within cEDS and hEDS. More recently, a study performed in the pediatric population did not show increased prevalence (Ritter et al., American Journal of Medical Genetics Part A, 173(6), 1467-1472, 2017). The purpose of this study was to review a large population of individuals with cEDS, hEDS, and hypermobility spectrum disorders to determine the frequency of MVP and ARD. A retrospective chart review of 209 individuals with echocardiograms was performed. Overall, 6.4% (13/209) had MVP and 1.6% (3/189) were found to have ARD. Although the presence of MVP is higher than what has been reported in the general population, no patients had severe MVP or required surgical intervention. No patients in this cohort had an aortic root diameter requiring surgical repair. Based on the results of this study and previous studies, routine echocardiograms to assess for valvular diseases and ARD may not be necessary unless warranted by presence of symptoms or family history., (© 2018 Wiley Periodicals, Inc.)