Genomic Answers for Kids: Toward more equitable access to genomic testing for rare diseases in rural populations.

Next-generation sequencing has revolutionized the speed of rare disease (RD) diagnoses. While clinical exome and genome sequencing represent an effective tool for many RD diagnoses, there is room to further improve the diagnostic odyssey of many RD patients. One recognizable intervention lies in increasing equitable access to genomic testing. Rural communities represent a significant portion of underserved and underrepresented individuals facing additional barriers to diagnosis and treatment. Primary care providers (PCPs) at local clinics, though sometimes suspicious of a potential benefit of genetic testing for their patients, have significant constraints in pursuing it themselves and rely on referrals to specialists. Yet, these referrals are typically followed by long waitlists and significant delays in clinical assessment, insurance clearance, testing, and initiation of diagnosis-informed care management. Not only is this process time intensive, but it also often requires multiple visits to urban medical centers for which distance may be a significant barrier to rural families. Therefore, providing early, "direct-to-provider" (DTP) local access to unrestrictive genomic testing is likely to help speed up diagnostic times and access to care for RD patients in rural communities. In a pilot study with a PCP clinic in rural Kansas, we observed a minimum 5.5 months shortening of time to diagnosis through the DTP exome sequencing program as compared to rural patients receiving genetic testing through the "traditional" PCP-referral-to-specialist scheme. We share our experience to encourage future partnerships beyond our center. Our efforts represent just one step in fostering greater diversity and equity in genomic studies.

Incidental Detection of Malignancies With Cell-Free DNA Screening.

Cell-free circulating DNA is an evolving technology with important clinical applications in both obstetric care and oncology. In the challenging patient with pregnancy and co-existing malignancy, the utility of cell-free DNA both for aneuploidy screening and cancer identification is an area of active research. Understanding the physiology associated with circulating cell-free DNA and subsequent laboratory evaluation is critical for clinicians caring for the obstetric patient with cell-free fetal DNA screening results suggestive of malignancy. Ongoing research is necessary to determine best practices for the evaluation and management of these patients with promising applications in the advancement of precision medicine.

Informed consent for expanded carrier screening: Past, present, and future.

History, law, bioethics, and geocultural influences all have impacted the modern application of informed consent. It is a complex, multilayered process to communicate information and obtain voluntary patient permission before a health care intervention. Lack of provider education about genetic disorders, complexities of advanced genomic technologies, limited time during patient encounters, and low health literacy within a population all represent challenges to effective communication. There is no consensus on how informed consent in reproductive genetics is optimally obtained. Expanded carrier screening (ECS) is purposed to simultaneously test for a large list of diseases in a pan-ethnic manner. The increased use of ECS is driven by advances in genomic technologies, decreased cost, an improved understanding of single gene disorders, and in support of reproductive autonomy. Academic organizations recommend pretest counseling when patients consider ECS, yet best practice is not established. Ongoing research is needed to determine how optimally implement informed consent given the increased complexity of ECS.

Incidental Detection of Maternal Malignancy by Fetal Cell-Free DNA Screening.

Cell-free DNA is an advancing technology with increasing applications in screening, diagnosis, and treatment for several disease processes. The shared physiologic, genetic, and epigenetic characteristics of placental physiology and tumor development have become apparent to both clinicians and researchers. Maternal malignancy has been reported as a cause of false-positive prenatal cell-free DNA screening results. The detection of multiple aneuploidies or a single autosomal monosomy increases the chance for an underlying maternal malignancy when the result is discordant with fetal diagnostic testing. There is currently no consensus guideline on counseling and evaluation of patients with concern for malignancy from cell-free DNA testing. Furthermore, laboratories differ significantly in reporting policies, terminology, and in reporting strategies and methods used for unexpected or incidental findings. The ordering practitioner is therefore tasked to understand the policies of their laboratory of choice to provide adequate pretest and posttest genetic counseling. In pretest counseling, the potential for incidental or unexpected findings or nonreportable results should be explained. With an abnormal, unanticipated, or nonreportable result, posttest counseling should include a description of possible fetal or maternal diagnoses, including malignancy. Health care professionals should explain options for further evaluation and management, including a recommendation for fetal diagnostic testing. The medical workup recommended by various authors to evaluate cancer risk is based on consensus, experience, and expert opinion. These strategies should incorporate the patient's desire for information, cost, and family and personal medical history. Ongoing research and multi-disciplinary collaboration in this area is critical to identify best practices in management of complex results from this increasingly common screening test.

Search for Lepton Number and Flavor Violation in K

Searches for the lepton number violating K^{+}→π^{-}µ^{+}e^{+} decay and the lepton flavor violating K^{+}→π^{+}µ^{-}e^{+} and π^{0}→µ^{-}e^{+} decays are reported using data collected by the NA62 experiment at CERN in 2017-2018. No evidence for these decays is found and upper limits of the branching ratios are obtained at 90% confidence level: B(K^{+}→π^{-}µ^{+}e^{+})<4.2×10^{-11}, B(K^{+}→π^{+}µ^{-}e^{+})<6.6×10^{-11} and B(π^{0}→µ^{-}e^{+})<3.2×10^{-10}. These results improve by 1 order of magnitude over previous results for these decay modes.

Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.

Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.

Oromandibular dystonia: a diagnosis not to miss.

Oromandibular dystonia (OMD) is characterised by sustained or repetitive involuntary movements of the jaw, face, and tongue. People with the condition may present to their dentist, general practitioner, or a secondary care specialist with non-specific symptoms including jaw or facial pain, bruxism, subluxations or dislocations of the jaw; fractured teeth or dental restorations, or both; or jaw tremor. Many clinicians are not aware of the disorder and this can lead to delayed diagnoses, unnecessary complications, and inappropriate treatment. OMD is an important diagnosis not to miss because referral for specialist management can provide good long-term results. To aid early, accurate diagnosis, this paper focuses on the key clinical features of the disorder and its dental and medical mimics.

What are the required components of pre- and post-test counseling?

Prenatal care providers are faced with a myriad of decisions about how to offer genetic screening and testing in ways that are appropriate to their patient population and their workflow. Among the critical issues brought to the forefront of rapidly advancing genetic and genomic technologies is the importance of pre- and post-test counseling. This document is a synthesis of proceedings of a workshop sponsored by the American College of Obstetricians and Gynecologists, the American College of Medical Genetics and Genomics, and the Society for Maternal-Fetal Medicine, on January 24-25, 2017, during which invited experts discussed required components of pre- and post-test counseling and associated concerns in the provision of prenatal care.

Utility of Obtaining a Serum Basic Metabolic Panel in the Setting of a First-Time Nonfebrile Seizure.

New-onset nonfebrile seizures in an otherwise healthy child are common, affecting 25 000 to 40 000 U.S. children annually. We hypothesized seizure-provoking electrolyte disturbances such as hyponatremia, hypoglycemia, and hypocalcemia are uncommon in these children. From January 1, 2009 to May 31, 2009, 358 children aged 29 days to 18 years with a diagnosis code of 780.39 ("other convulsions" including "first time seizure," etc) were included for potential retrospective review. Children with known epilepsy and febrile seizures were excluded. Electrolytes were obtained in nearly all children with a history suggestive of an underlying abnormality (13 of 14, 93%) but also in half of children with a reassuring history (62 of 119, 52%). No child with an unremarkable history and exam was found to have electrolyte abnormalities falling below levels most likely to be associated with acute symptomatic seizures. Electrolytes are unlikely to be abnormal in an otherwise well-appearing child after a first-time nonfebrile seizure.

Screening for fetal aneuploidy.

Screening is currently recommended in pregnancy for a number of genetic disorders, chromosomal aneuploidy, and structural birth defects in the fetus regardless of maternal age or family history. There is an overwhelming array of sonographic and maternal serum-based options available for carrying out aneuploidy risk assessment in the first and/or second trimester. As with any screening test, the patient should be made aware that a "negative" test or "normal" ultrasound does not guarantee a healthy baby and a "positive" test does not mean the fetus has the condition. The woman should have both pre- and post-test counseling to discuss the benefits, limitations, and options for additional testing. Rapid advancements of genetic technologies have made it possible to screen for the common aneuploidies traditionally associated with advanced maternal age with improved levels of accuracy beyond serum and ultrasound based testing. Prenatal screening for fetal genetic disorders with cell-free DNA has transformed prenatal care with yet unanswered questions related to the financial, ethical, and appropriate application in the provision of prenatal risk assessment.

Changing indications for invasive testing in an era of improved screening.

Prenatal diagnostic testing is available for a growing number of disorders. The goal of prenatal diagnosis was initially focused on the identification of Down syndrome in women aged 35 years and older, but invasive prenatal genetic techniques can now detect a far broader array of conditions. The risks of invasive procedures have also decreased over time. Advances in genomic medicine allow testing for smaller but significant chromosomal abnormalities known as copy number variants, in addition to major aneuploidies and structural rearrangements. Molecular DNA techniques can detect many single-gene conditions. In the future, it is likely that whole-exome and whole-genome sequencing will be applied to prenatal genetic testing to allow identification of yet more genetic disorders. With advances in technology, the indications for testing have likewise evolved far beyond recommendations based solely on maternal age to include a more patient-centered view of the goals of prenatal testing.

Improved Measurement of the π→eν Branching Ratio.

A new measurement of the branching ratio R_{e/µ}=Γ(π^{+}→e^{+}ν+π^{+}→e^{+}νγ)/Γ(π^{+}→µ^{+}ν+π^{+}→µ^{+}νγ) resulted in R_{e/µ}^{exp}=[1.2344±0.0023(stat)±0.0019(syst)]×10^{-4}. This is in agreement with the standard model prediction and improves the test of electron-muon universality to the level of 0.1%.

An uncommon dermatophyte infection: two cases of cutaneous infection with Trichophyton verrucosum.

Zoophilic dermatophytes can cause highly inflammatory cutaneous infections. Cattle represent the largest reservoir for the zoophilic dermatophyte Trichophyton verrucosum. Effective vaccination programmes have contributed to a low rate of livestock infection in central and northern Europe, and T. verrucosum infection is relatively more common in southern Europe and in Arabic countries. Transmission to humans typically results from direct contact with infected livestock. It may also be transmitted from person to person. We report two cases of T. verrucosum skin infections in Irish farmers. In both cases, effective treatment was delayed due to misdiagnosis of the condition as a bacterial infection in the primary care setting. Both cases responded rapidly to treatment with oral terbinafine. Culture of T. verrucosum can take 3 weeks or longer to grow, therefore a high index of clinical suspicion is necessary, and skin scrapings for potassium hydroxide microscopy and culture are essential for accurate diagnosis.

How to deal with petabytes of data: the LHC Grid project.

We review the Grid computing system developed by the international community to deal with the petabytes of data coming from the Large Hadron Collider at CERN in Geneva with particular emphasis on the ATLAS experiment and the UK Grid project, GridPP. Although these developments were started over a decade ago, this article explains their continued relevance as part of the 'Big Data' problem and how the Grid has been forerunner of today's cloud computing.

Noninvasive prenatal screening by next-generation sequencing.

Noninvasive prenatal screening (NIPS) has emerged as a highly accurate method of screening for fetal Down syndrome, with a detection rate and specificity approaching 100%. Challenging the widespread use of this technology are cost and the paradigm shift in counseling that accompanies any emerging technology. The expense of the test is expected to decrease with increased utilization, and well beyond the current NIPS technology, its components (fetal genome measurements, sequencing technology, and bioinformatics) will be utilized alone or in combinations to interrogate the fetal genome. The end goal is simple: to offer patients information early in pregnancy about fetal genomes without incurring procedural risks. This will allow patients an opportunity to make informed reproductive and pregnancy management decisions based on precise fetal genomic information.

Nanoparticle composites for printed electronics.

Printed Electronics is a rapidly developing sector in the electronics industry, in which nanostructured materials are playing an increasingly important role. In particular, inks containing dispersions of semiconducting nanoparticles, can form nanocomposite materials with unique electronic properties when cured. In this study we have extended on our previous studies of functional nanoparticle electronic inks, with the development of a solvent-based silicon ink for printed electronics which is compatible with existing silver inks, and with the investigation of other metal nanoparticle based inks. It is shown that both solvent-based and water-based inks can be used for both silver conductors and semiconducting silicon, and that qualitatively there is no difference in the electronic properties of the materials printed with a soluble polymer binder to when an acrylic binder is used.

Maternal hemolysis after intravenous immunoglobulin treatment in fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Intravenous immunoglobulin (IVIG) is a therapeutic agent used to prevent fetal thrombocytopenia in those pregnancies identified to be at risk for fetal and neonatal alloimmune thrombocytopenia. Although generally considered a safe medication, hemolytic anemia is a known side effect of IVIG treatment that may result in maternal medical complications. CASES: We present three cases of IVIG-induced maternal anemia from separate institutions that occurred during treatment for fetal and neonatal alloimmune thrombocytopenia and resolved after discontinuation or alteration of therapy. None of the treated fetuses had thrombocytopenia at birth. CONCLUSION: There is a potential for hemolysis when prescribing IVIG. We recommend laboratory monitoring for hemolytic anemia and suggest options for management including drug modification or cessation of therapy.

Processing LHC data in the UK.

The Large Hadron Collider (LHC) is one of the greatest scientific endeavours to date. The construction of the collider itself and the experiments that collect data from it represent a huge investment, both financially and in terms of human effort, in our hope to understand the way the Universe works at a deeper level. Yet the volumes of data produced are so large that they cannot be analysed at any single computing centre. Instead, the experiments have all adopted distributed computing models based on the LHC Computing Grid. Without the correct functioning of this grid infrastructure the experiments would not be able to understand the data that they have collected. Within the UK, the Grid infrastructure needed by the experiments is provided by the GridPP project. We report on the operations, performance and contributions made to the experiments by the GridPP project during the years of 2010 and 2011--the first two significant years of the running of the LHC.